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© Birkhäuser Verlag, Basel, 2004

Inflamm. res. 53 (2004) 424– 441


1023-3830/04/090424-18 Inflammation Research
DOI 10.1007/s00011-004-1283-z

Understanding human dendritic cell biology through gene profiling


Z. Tang and A. Saltzman
Aventis Pharmaceuticals, Immunology Platform Department, Mail Stop G303A, Routes 202-206, Bridgewater, NJ 08807, USA, Fax: 908 231 3586
e-mail: alan.saltzman@aventis.com

Received 25 February 2004; accepted by A. Falus 14 April 2004

Abstract. Dendritic cells are potent antigen presenting cells human dendritic cells in Table 1. This review will focus on
whose function has been associated with a variety of analyzing what we have learned from such studies, primarily
immunological disorders. Because of their relevance to focusing on the human dendritic cell types, and what addi-
human disease, extensive efforts have been made to gain a tional information can be gained from such studies.
better understanding of their biology. One aspect of these
efforts has been in the identification of pertinent molecules
expressed in these cells through gene profiling experiments Models used for dendritic cell profiling
and proteomics. In this review, we summarize the results
from the various profiling studies that have been done with Until approximately ten years ago, it was challenging to per-
human dendritic cells. We focus on molecules, which have form studies on human dendritic cells because of the diffi-
been confirmed by other methods, such as quantitative PCR, culty to isolate them. This changed with the development of
or have been identified in multiple profiling studies to be systems for the differentiation of dendritic cells from pre-
expressed in the respective dendritic cell type. Through such cursor cells that are easier to isolate [33, 34]. One of the
profiling experiments and subsequent analysis, interesting more common methods for preparing dendritic cells is by
molecules have been identified which can be further studied the differentiation of monocytes with IL-4 and GM-CSF to
to determine their role in dendritic cell biology. immature dendritic cells. Although less common, CD34+
stem cells have also been used as a source for precursor cells
Key words: Dendritic cells – Gene profiling – Human in dendritic cell profiling studies.
Overall, immature dendritic cells are defined as cells that
have a potent ability to take up and process antigen [1, 2].
Immature dendritic cells are characterized by a number of
Introduction criteria. First, is an increase in the ability of these cells to take
up antigen, commonly assayed by the uptake of FITC-coated
Dendritic cells are generally acknowledged to be the most dextran. Secondly, there is a characteristic morphological
potent antigen presenting cell type known (as reviewed in [1, change, from round shaped cells to an irregular cell shape
2]). One of the reasons for this is because of their ability to with spine-like projections. Lastly is the increase in cell sur-
activate T lymphocytes at effector: target ratios much lower face markers, such as mannose receptor and HLA-DR, and a
than other types of antigen presenting cells, such as decrease in the expression other cell surface markers, such as
macrophages and B cells. In addition to this property, den- CD14. Another criteria, which is used, but is more relevant to
dritic cells are capable to activate a wider range of T cells the mature dendritic cell, is the ability of the dendritic cell to
than other known antigen presenting cells. In particular, they promote T cell proliferation through an alloreactive stimula-
are unique in their ability to activate naïve T cells. tion.
Because of these capabilities, in addition to others, As shown in Table 1, a number of laboratories have used
increased dendritic cell activity has been associated a wide GM-CSF/IL-4 treated monocytes as a method to prepare
range of immunological based disorders, including asthma dendritic cells for profiling. However, because of the various
[3], rheumatoid arthritis [4], lupus [5], and multiple sclerosis modifications used in this protocol, such as amount and
[6]. Therefore, much effort has been investigated in learning source of cytokine used, length of time for differentiation,
more about the biology of the dendritic cells. Some of this and cell media used, each of these reports can give a differ-
effort has focused on the profiling of genes expressed in ent set of genes induced upon differentiation. Depending on
these cells. This has led to approximately 40 different profil- the report, as indicated in Table 1, one or more of the criteria
ing studies on dendritic cells, which is summarized for the listed in the previous paragraph are used to define the differ-
entiated monocytes as being immature dendritic cells. One
Correspondence to: A. Saltzman assumption is that although protocols may change, if the
Vol. 53, 2004 Human dendritic cell profiling 425

Table 1. Summary of published dendritic cell gene profiling and proteomics studies.

Reference Method for Characterization Method for Characterization Profiling Comparison done
differentiation to/ of immature maturation/ of matured/ Assay
isolation of dendritic cells treatment of treated
immature immature immature
dentritic cells dentritic cells dendritic cells

Hashimoto S-I, et al. 1) Monocytes: Morphology, N/A N/A SAGE Comparison of


1999 [7] GM-CSF/IL-4/ cell surface monocytes/
TNF-a + 7.5% FCS markers immature dendritic
in RPMI-1640 cells/macrophages
2) Monocytes:
GM-CSF 7.5% FCS
in RPMI-1640
(macrophages)
Dietz AB, et al. Monocytes: Cell surface IL-6/TNF-a/IL-1b/ Cell surface marker, Microarray Immature dendritic
2000 [8] GM-CSF/IL-4 + 1% markers PGE2 (3 days) cytokine production, cells/mature dendritic
human plasma in T cell alloreactive cells
XVIVO-15 stimulation
Hashimoto S-I, et al. Monocytes: GM- Morphology, cell LPS (48 h) Morphology, cell SAGE Immature dendritic
2000 [9] CSF/IL-4 + 7.5% surface markers surface markers cells/mature dendritic
FCS in RPMI-1640 cells
Angénieux C, et al. Monocytes: GM- Morphology, cell N/A N/A Differential Immature dendritic
2001 [10] CSF/IL-4 + 10% surface markers display cells/monocytes
FCS in RPMI-1640 Proteomics
Baltathakis J, et al. 1) Monocytes: Cell surface LPS (48 h) Cell surface Microarray Mature dendritic cells/
2001 [11] GM-CSF/IL-4 + 10% markers, T cell markers, T cell macrophages/
FCS in RPMI-1640 alloreactive alloreactive monocytes
2) Monocytes: stimulation stimulation
M-CSF + 10% FCS
in RPMI-1640
(macrophage)
Bleharski JR, et al. Monocytes: GM-CSF/ Unknown CD40L (24 h) Cell surface cDNA Mature dendritic cell
2001 [12] IL-4 + 10% FCS in markers, cytokine subtraction cDNA subtracted
RPMI-1640 production with immature
dendritic cell cDNA
Huang Q, et al. Monocytes: GM-CSF/ Cell surface 1) Escherichia coli Cell surface Microarray Immature dendritic
2001 [13] IL-4 + 10% FCS in markers 2) Candida albicans markers cells/dendritic
RPMI-1640 3) Influenza cells matured with
4) LPS respective individual
5) Poly I:C agents at respective
6) Mannan time points
(1, 2, 4, 8, 12, 18,
24, and 36 h for the
respective stimulus)
Lapteva N, et al. Monocytes: GM-CSF/ Morphology, cell N/A N/A Microarray Monocytes/immature
2001 [14] IL-4 + 10% FCS in surface markers dendritic cells
AIM-V
Lapteva N, et al. Monocytes: GM-CSF/ Cell surface a-galactosyl- Cell surface Microarray Treated/untreated
2001 [15] IL-4 + 10% FCS in markers ceramide (48 h) markers dendritic cells
AIM-V
Lapteva N, et al. Monocytes: GM-CSF/ Morphology, cell TNF-a (48 h) Morphology, cell Microarray Immature dendritic
2001 [16] IL-4 + 10% FCS in surface markers surface markers cells/mature
AIM-V dendritic cells
Le Naour F, et al. Monocytes: GM-CSF/ Morphology, cell TNF-a (7 days) Morphology, cell Microarray and Monocyte/immature
2001 [17] IL-4 in XVIVO-15 surface markers surface markers proteomics dendritic cells/mature
dendritic cells
Moschella F, et al. 1) Monocytes: Cell surface 1) TNF-a (48 h) Cell surface Microarray Immature dendritic
2001 [18] GM-CSF/IL-4 in markers 2) CD40L (48 h) marker cells/dendritic cells
AIM-V 3) IFNg (48 h) matured with
2) Monocytes: respective individual
GM-CSF/IL-7 in agents
AIM-V
426 Z. Tang and A. Saltzman Inflamm. res.

Table 1. (continued)

Reference Method for Characterization Method for Characterization Profiling Comparison done
differentiation to/ of immature maturation/ of matured/ Assay
isolation of dendritic cells treatment of treated
immature immature immature
dentritic cells dentritic cells dendritic cells

Ahn JH, et al. 1) Monocytes: Morphology, 1) Monocyte Morphology, cell Microarray and 1) Microarray:
2002 [19] GM-CSF-IL-4 + cell surface conditioned media+ surface markers cDNA different dendritic
human serum in markers TNF-a (monocyte- subtraction cell types, immature
RPMI-1640 derived dendritic and mature and
2) CD11c- cells) (2 days) CD34+ cells
(plasmacytoid) 2) IL-2/ CD40L 2) cDNA Subtraction:
dendritic cells) (in RPMI-1640 + Pool of samples
3) CD34 + cells; 10% human serum) #2, 3, and 4
TNF-a/IL-3 + human (plasmacytoid) (immature) cDNA
serum in RPMI-1640; (5 days) subtracted with
CD1a + CD14- sorted 3) Time of differen- cDNA from B cells,
4) CD34 + cells; tiation (8 day vs monocytes, and
TNF-a/GM-CSF + 18 days) (CD1a + T cells
human serum in CD14-sorted)
RPMI-1640; 4) Time of differen-
CD1a-CD14 + sorted tiation (8 day vs
18 days) (CD1a –
CD14 + sorted)
Lapteva N, et al. Monocytes: GM-CSF/ Morphology, cell 1) Angiotensin II Cytokine Microarray Immature dendritic
2002 [20] IL-4 + 10% FCS in surface markers (6 h) production cells untreated and
AIM-V 2) Captopril (6 h) treated with
respective agent
Lindstedt M, et al. Monocytes: GM-CSF/ Morphology, cell Monocyte Morphology, cell Microarray Immature dendritic
2002 [21] IL-4 + 10% FBS in surface markers conditioned media + surface markers cells/dendritic cells
RPMI-1640 TNF-a/IL-1b matured at respective
(8, 24, and 48 h) time points
Matsunga T, et al. Monocytes: GM-CSF/ Cell surface 1) LPS Cell surface Differential Immature dendritic
2002 [22] IL-4 + 10% FCS in markers 2) TNF-a markers display cells/dendritic cells
RPMI-1640 3) TGF-b matured with
(1, 4, and 24 h) respective individual
agents at respective
time points
Rissoan M-C, et al. 1) Plasmacy-toid Unknown 1) IL-3/CD40L Unknown cDNA a) Pool of plasmacy-
2002 [23] dendritic cells isolated (plasmacytoid) (24, subtraction toid dendritic cell
from tonsil 48, 72, and 96 h) cDNA (both CD40L
2) Monocytes: 2) CD40L treated and untreated)
GM-CSF/IL-4 + 10% (monocyte derived subtracted with
FCS in RPMI-1640 dendritic cells) mature monocyte
(16 and 48 h) derived dendritic cell
cDNA
b) Immature plasma-
cytoid dendritic cell
cDNA subtracted
with immature
monocyte derived
dendritic cell cDNA
Schlaak JF, et al. Monocytes: GM-CSF/ Unknown IFN-a2a (8 h) Unknown Microarray Treated/untreated
2002 [24] IL-4 + 10% FCS in dendritic cells
RPMI-1640
Chaussabel D, et al. 1) Monocytes: Cell surface Parasites (16 h): Cell surface marker Microarray Dendritic cells and
2003 [25] GM-CSF/IL-4 + 10% markers 1) Brugia malayi macrophages treated
human serum in 2) Toxoplasma and untreated with
RPMI-1640 gondii respective individual
2) Monocytes: 3) Leishmania agents
M-CSF + 10% human major
serum in RPMI-1640 4) Leishmania
(macrophage) donovani
Vol. 53, 2004 Human dendritic cell profiling 427

Table 1. (continued)

Reference Method for Characterization Method for Characterization Profiling Comparison done
differentiation to/ of immature maturation/ of matured/ Assay
isolation of dendritic cells treatment of treated
immature immature immature
dentritic cells dentritic cells dendritic cells

Hashimoto S-I, et al. 1) Monocytes: Morphology, cell LPS (48 h) Morphology, cell SAGE Comparison of
2003 [26] GM-CSF/IL-4 + 7.5% surface markers (monocyte derived surface markers immature dendritic
FCS in RPMI-1640 dendritic cells) cells, mature
2) Monocytes: dendritic cells,
GM-CSF/IL-4/ langerhans-like cells,
TGF-b+ 7.5%FCS in unstimulated, mono-
RPMI-1640 cytes, LPS stimulated
(Langerhans like-cells) monocytes, unstimu-
lated macrophages,
LPS stimulated
macrophages, naïve
CD4 positive T cells,
memory CD4 positive
T cells, TH1 cells,
TH2 cells, NK cells,
unactivated B cells
and activated B cells
Izmailova E, et al. Monocytes: Morphology, cell 1) HIV-1 infection TAT mRNA Microarray Untreated/HIV-1/
2003 [27] GM-CSF/IL-4 + 10% surface markers (1, 3, and 10 days) expression, TAT-adenovirus/
FCS in RPMI-1640 2) TAT-adenovirus cytokine control infected
(4, 10, 16, and 30 h) production dendritic cells at
given time points
Ju X-S, et al. CD34+ cells; Morphology, cell TNF-a (6 days) Morphology, cell Microarray Progenitor/
2003 [28] GM-CSF-IL-4 + 10% surface markers, surface markers, immature dendritic
FCS in RPMI-1640 endocytosis, endocytosis, T cell cells/mature
T cell alloreactive alloreactive dendritic cells
stimulation stimulation
Messmer D, et al. Monocytes: Cell surface 1) LPS (24 and 48 h) Cell surface Microarray Immature dendritic
2003 [29] GM-CSF/IL-4 + 1 % markers 2) CD40L (24 and marker, cytokine cells/dendritic cells
human plasma in 48 h) production matured with
RPMI-1640 3) IL-6/TNF-a/ respective individual
IL1b/ PGE2 (24 agents at respective
and 48 h) time points
Moschella F, et al. 1) Monocytes: Cell surface N/A N/A Microarray Dendritic cells
2003 [30] GM-CSF/IL-4 in markers, T cell differentiated under
AIM V medium alloreactive respective protocol
2) Monocytes: stimulation
GM-CSF/IFN-a2b in
AIM-V
Skelton L, et al. Monocytes: Morphology, cell Monocyte Morphology, cell Microarray Immature/mature
2003 [31] GM-CSF/IL-4 + 10% surface markers, conditioned media surface markers, dendritic cells
FCS in RPMI 1640 endocytosis, (72 h) endocytosis, T cell
T cell alloreac- alloreactive
tive stimulation stimulation
Türeci Ö, et al. Monocytes: Cell surface CD40L (2 and Cell surface marker Microarray Immature dendritic
2003 [32] GM-CSF/IL-4 + 10% markers 40 h) cells/mature
FCS in RPMI-1640 dendritic cells

immature dendritic cells isolated share the same properties their ability to present antigen is induced upon maturation,
(i.e., antigen uptake ability), then the same genes relevant for the ability of dendritic cells to take up antigen is decreased.
this function should be equally regulated. However, since Therefore, the cell surface expression of molecules relevant
some of these properties are not universally tested prior to in this process, such as the mannose receptor and DEC205, is
profiling, this type of assumption has a certain level of risk. decreased. Maturation of dendritic cells occurs through their
Maturation of immature dendritic cells is defined as their interaction with infectious agents, cytokines, or contact with
increased ability to present antigen and activate T cells [1, 2]. other cell types. Infectious agents or components from such
Consequently, accessory molecules necessary for this T cell agents used for profiling studies include LPS [9, 11, 13, 22,
activation ability, such as CD80 and CD86, are upregulated 26, 29] poly I:C [13], bacteria (e.g., Escherichia coli) [13],
on the surface of the mature dendritic cell. Furthermore, as yeast (e.g. Candida albicans) [13], parasites (e.g. Leishma-
428 Z. Tang and A. Saltzman Inflamm. res.

nia major) [25], and viruses (e.g. influenza virus, HIV-1) [13, in using dendritic cells differentiated in vitro from precursor
27]. Cytokines and molecules reflecting cell-cell contact that cells.
have been used to mature dendritic cells for profiling studies One other class of dendritic cells that are being studied in
include TNF-α [8, 16–19, 21, 22, 28, 29] and CD40L [12, profiling experiments is dendritic cells that reside in tissue.
18, 19, 23, 29, 32]. One example of such cells are Langerhans cells of the skin,
Although the ultimate definition of maturation, ability to which are important in being amongst the primary cells
present antigen and activate T cells, is achieved by all of these which are first exposed to foreign antigen [2]. Profiling
maturation agents, the signaling mechanisms involved are experiments on these cell types are hampered by the difficul-
quite different. Thus, stimulation of dendritic cells with ty to isolate them. However, in vitro models of differentiating
infectious agents would activate receptors and intracellular these cells from CD34+ stem cells have been developed for
signaling pathways associated with innate immunity, such as Langerhans cells [46]. These models have been utilized as
toll-like receptors (TLR) [35, 36] quite different from the cell sources for profiling studies to understand their relation-
pathways activated by TNF-α [37]or CD40L [38]. For exam- ship to other types of dendritic cells [26].
ple, unlike TNF-α or CD40L, TLR stimulation can directly
activate IRF3 leading to type 1 interferon induction [39].
Furthermore, the pathways stimulated by the particular infec- Discoveries made from profiling studies of dendritic cells
tious agent diverge amongst the different TLR activated.
Thus, while the stimulation of TLR4 or TLR5 in dendritic There are a number of different objectives that could be
cells can lead to the activation of p38 and JNK1/2 and the achieved with profiling experiments in general and in partic-
subsequent induction of IL-12 production, TLR2 stimulation ular with dendritic cells. First would be the identification of
induces the activation of ERK1/2, leading to the suppression molecules involved in pathways that are known to be impor-
of IL-12 production [40]. tant in dendritic cell function. These could be molecules that
Another consideration is the context in which the stimu- are already known based on previous studies, for example the
lation occurs. For example, CD40L stimulation would most expression of the mannose receptor in immature dendritic
likely occur in the draining lymph nodes when dendritic cells cells or the expression of CD86 in mature dendritic cells, or
are interacting with naïve T cells, unlike where infectious novel molecules. Secondly, there would be the identification
agent or TNF-α induced maturation would occur. Although of pathways that may be overlooked, but serve an important
the primary response, induction of T cell activation capaci- function in immature dendritic cell function. For example,
ties, would be induced in both circumstances, other proper- molecules involved in cytoskeletal reorganization for vesicu-
ties (for example types of chemokines induced) would be lar movements in immature dendritic cells. A third objective
predicted to be different due to the environment where the would be to obtain a broader understanding of dendritic cell
response is taking place. function and its affects on other cell types. An example of
In addition to in vitro models for dendritic cell profiling, this would be the identification of chemokines produced by
recently, taking advantage of the cumulative knowledge in dendritic cells that attract cell types not commonly associat-
the identification and isolation of dendritic cells produced in ed with dendritic cells. Fourth would be the identification of
vivo, profiling studies have been initiated with these isolated novel molecules in dendritic cells that regulate dendritic cell
dendritic cell types [19, 23]. There are two types of human function. A good example of this is GPR105 that was identi-
dendritic cells that have been identified from blood, a fied on immature dendritic cells and whose ligand, UDP glu-
CD11c–, CD123+ plasmacytoid and a CD11c+, CD123– mye- cose, was found to mature dendritic cells [31]. Lastly, is the
loid dendritic cell type [41]. The plasmacytoid dendritic cells identification of novel pathways that exist in dendritic cells.
are potent antigen presenting cells [41, 42]. They are best Although a large number of genes have been identified in
known for their capacity to produce high levels of interferon profiling studies to be expressed in immature or mature
α upon stimulation [43], unlike myeloid dendritic cells. They human monocyte derived dendritic cells, the one caveat to
are also distinguished from myeloid dendritic cells by their these studies is that most of the genes identified have not
expression of distinct TLR , primarily TLR7 and TLR9, in been confirmed to be regulated by some more quantitative
which the latter is activated by CpG motif containing DNA means, such as by northern analysis or quantitative PCR.
molecules [44]. Plasmacytoid dendritic cell are increasing Among the genes identified by profiling experiments that
being considered playing a role in the antiviral responses and have been confirmed to be expressed in immature dendritic
in diseases associated with high levels of type I interferons, cells include antigen uptake receptors (mannose receptor
such as lupus [45]. The myeloid class of dendritic cells more [19]), antigen presentation molecules (CD1e [10]), cell sig-
closely represents the dendritic cells that are obtained by naling molecules (alpha catenin [14], AS1 protein [15]),
the differentiation of precursor cells with GM-CSF/IL-4 chemokines (MCP-4 [7, 10, 19], CCL15 [31], CCL23 [31],
[41]. They have a strong ability to take up, process, and TARC [7, 19]), cytoskeleton associated molecules (AP-50
present antigen [41]. They express TLR distinct from the [10], dihydropyrimidinase related protein 2 [10], gelsolin
plasmacytoid dendritic cells, in particular TLR2 and TLR4 [10], arp2/3 protein complex subunit p16-Arc [15], clathrin
[44]. Thus myeloid dendritic cells, unlike plasmacytoid den- associated protein [15]), cytokines (TNF-α [14]), ion chan-
dritic cells, are capable of being stimulated by agents such nels/transporters (MRP-4 [10], voltage dependent anion
as LPS and zymosan. Overall, because myeloid and plasma- channel [15]), metabolism associated molecules (inosinicase
cytoid dendritic cells are isolated directly from the body, [7], cytochrome b561 [10], phosphofructokinase [7,15], core
the profiling studies using these cells should be more rele- I protein [15], fatty acid synthetase [15], lipase A[19]), pro-
vant in understanding the role of dendritic cells in vivo than teases and protease inhibitors (hepatocyte growth factor acti-
Vol. 53, 2004 Human dendritic cell profiling 429

vator inhibitor [7], cathepsin C [7], metalloproteinase [7], ulating the ability of dendritic cells to differentiate T helper
kunitz-type protease inhibitor [15], CD26 [10]), receptors cells [50, 51]. Overall, both the profiling data and the litera-
(CD32 [10], TNFR II [14], CCR1 [31], CCR5 [31], GPR105 ture data tend to complement each other to support a relevant
[31]), transcription factors (aconitase [15]), and other mis- role for lipid presentation in dendritic cell biology.
cellaneous proteins (CD63 [10], motor protein [15], high For dendritic cells matured with agents such as LPS,
density lipoprotein binding protein [15], osteopontin[19], TNF-α, or CD40L; this analysis revealed, despite the differ-
GPNMB [19]). As similar set of genes initially found by pro- ences in signaling induced by the different stimuli, a com-
filing have been confirmed to be expressed in mature den- mon pattern of regulation. Thus LPS and TNF-α induced a
dritic cells such as apoptosis-associated molecules (NAIP significant number of genes for various chemokines and
[22], IAP-B [32], IAP-C [22, 32]) cell signaling molecules transcription factors. The induction of chemokine genes indi-
(DAPP-1 [32]), chemokines (MDC [12], MIG [12], CCL18 cates a role of dendritic cells for attracting different immuno-
[26], TARC [31, 32], MIP-1a [32], MIP-1b [32], MIP-2a cytes to the site of inflammation. The production of T cell
[32], MIP2b [32], IL-8 [32], MGSA [32], MIP-1d [32], attractant chemokines has been reported previously [52] and
RANTES [32], TARC [32],) cytokines (IL-12p40 [9, 12], IL- is not surprising considering their role in T cell activation.
12p35 [9], EBI3 [9]), cytoskeleton associated molecules However, the upregulation of neutrophil chemoattractants
(actin-bundling protein [9], kinesin-2 [32]), metabolism implies a potential role of dendritic cells in neutrophil func-
associated molecules (MT2A [32]), proteases and protease tion or visa versa. This prospective relationship between
inhibitors (cystatin F [9], PSMA3 [22]), receptors (CCR7 [9, dendritic cells and neutrophils has not been commonly sug-
31]), T cell activation molecules (SLAM [12]), transcription gested. Recently it has been reported that activated neu-
factors (TFEC [22], IRF-1 [32], IRF-4 [32]), and other mis- trophils stimulate dendritic cells maturation and cytokine
cellaneous molecules (HEM45 [9], DC-LAMP [9], IFN production [53]. However, very little else has been published
inducible protein p27 [9], TrpTS [22], CD63 [22], clusterin and thus this area may be of potential value, at least based on
[32]). the profiling studies.
Another approach to discern what genes identified by The induction of genes for transcription factors indicates
profiling studies are truly differentially expressed in human that dendritic cell maturation involves a complex set of regu-
monocyte derived dendritic cells, either immature or matured latory events with multiple transcription factors being
with a respective agent, would be assume that such genes involved. This regulation of genes for transcription factors
would be identified in multiple independent studies. We include transcription factors commonly associated with LPS
therefore compared the results from various profiling studies and TNF-α signaling, such as NFκB components and IRF
to identify genes or proteins that were found to be differen- transcription factors, and additional transcription factors not
tially expressed in more than one independent study for the commonly associated with their signaling, such as STAT
same condition (immature dendritic cell [7, 10, 14, 17–19, molecules.
28]-Table 2; dendritic cells matured with LPS [9, 13, 29]- As indicated above, one of the more exciting areas of den-
Table 3; dendritic cells matured with TNF-α [8, 16–19, 21, dritic cell research is the recent profiling of dendritic cells
28]-Table 4; and dendritic cells matured with CD40L [12, 18, isolated from blood. Although a limited number of studies
32]-Table 5). Because of the different names, GenBank have been done [19, 23], some genes have been identified by
accession numbers, etc. used by the different publications to profiling that have been verified by other means, such as
denote their gene of interest, we decided to use LocusLink CD62L, CD123, CXCR4, Eph-B1, spi-B transcription fac-
[47] abbreviations and identification numbers in the tables as tor, ILT7, and a number of novel molecules [23]. One of these
a method to unify the various definitions. We also gave a proteins, spi-B, was further shown, by overexpressing the
brief summary of the protein coding for the gene, based on protein in hematopoietic progenitor cells, to be involved in
information obtained from Locus Link [47] or Online plasmacytoid dendritic cell development [54].
Mendelian Inheritance in Man (OMIM) [48]. Although it is interesting to speculate on the role these
In such an analysis for immature dendritic cells, there molecules have in dendritic cell function, experiments
were a number of genes identified (Table 2) which were con- addressing their specific functions in dendritic cell biology
firmed to be regulated in other studies, such as CD1e, MCP- are limited. For cell surface molecules, activating or inhibito-
4, TARC, and TNF-α. In addition, there were a number of ry antibodies could be used to discern the function of such
genes expressed in immature dendritic cells which were for molecules on dendritic cells. An example of such work is in
particular protein families. For example, a number of genes the case of the identification of SLAM expression on mature
for proteins involved in lipid transport were found to be dendritic cells [12]. In these studies, the authors found that
reproducibly upregulated when monocytes were differentiat- stimulatory antibodies to SLAM enhanced the expression of
ed to dendritic cells. These molecules, along with the find- proinflammatory cytokines from dendritic cells [12]. In cases
ings of the upregulation of genes for different CD1 subfami- where the ligand is known for the receptor, the role a receptor
ly molecules and lipid metabolizing molecules, implies the has with dendritic cells could be discerned, as described above
important role non-peptide antigen presentation may have for GPR105 using its ligand UDP-glucose [31].
with dendritic cells. Indeed, CD1 mediated lipid presentation However, for most other molecules, the only way that the
and activation of T cells has been speculated to be an early function of a given molecule could be determined would be
and efficient adaptive immune response [49]. In addition, it to genetically modulate the expression or the function of the
has been shown that interaction of dendritic cells with CD1 protein in the dendritic cell. To do this, the gene, expressing
restrictive T cells can be an important influence in the regu- the wild-type protein or a dominant negative form of the pro-
lation of dendritic cell cytokine production and thereby mod- tein would need to be introduced into dendritic cells. A num-
430 Z. Tang and A. Saltzman Inflamm. res.

Table 2. Upregulated genes identified in multiple profiling studies following differentiation of monocytes to dendritic cells.

Locus Link Name Locus Link ID Additional names Description

Antigen presentation/processing
CD1a 909 glycolipid presentation
CD1c 911 glycolipid presentation
CD1e 913 membrane protein involved in the presentation of glycolipids
CD74 972 HLA-DR-gamma, MHC class II antigen presentation
invariant gamma chain
HLA-DPA1 3113 MHC class II DP alpha 1, antigen presentation
HLA-SB alpha
HLA-DRA 3122 major histocompatibility HLA class II subunit involved in antigen presentation
complex, class II, DR alpha
precursor
Cell signaling
CTNNA1 1495 alpha catenin associated with signal induction via cell adhesion
DUSP1 1843 dual-specificity phosphatase 1 serine/threonine phosphatase which can inactivate MAP kinase
GNAI2 2771 guanine nucleotide binding G-protein alpha subunit
protein (G protein), alpha
inhibiting activity polypeptide 2
GUK1 2987 guanylate kinase 1 enzyme which phosphorylates GMP to GDP
LYN 4067 v-yes-1, Yamaguchi sarcoma tyrosine kinase involved in receptor signal transduction
viral related oncogene homolog
SLA 6503 SLAP, Src-like adapter protein adapter protein involved in receptor signaling
Cell survival/apoptosis/proliferation
GAS6 2621 growth arrest-specific protein 6, protein thought to be involved in cell proliferation
AXL stimulatory factor
SEMA3C 10512 semaphorin E secreted protein associated with cell survival and morphogenesis
Chemokines
CCL5 6352 RANTES, SCYA5 chemoattractant for memory T cells, monocytes, and eosinophils
CCL13 6357 MCP-4,SCYA-13 chemoattractant for basophils, T cells, monocytes, and eosinophils
CCL17 6361 TARC, SCYA17 T cell chemoattractant
CCL18 6362 PARC, MIP-4, SCYA18 T cell chemoattractant
CCL22 6367 MDC, SCYA22, STCP-1 NK cell, activated T cell, and dendritic cell chemoattractant

Cytokines/hormones
CSF1 1435 colony stimulating macrophage cytokine
factor 1, MCSF
IL1B 3553 interleukin 1, beta inflammatory cytokine
IL1RN 3557 interleukin 1 receptor antagonist for interleukin 1 receptor
antagonist, IL1RA
TGFB1 7040 transforming growth growth factor
factor beta 1
TNF 7124 TNFa, tumor necrosis proinflammatory cytokine
factor alpha
Lipid transport
APOC1 341 apolipoprotein C-I involved in lipid transport
APOE 348 apolipoprotein E protein involved in the transport of cholesterol and other lipids
FABP4 2167 fatty acid binding protein 4 intracellular protein involved in fatty acid uptake,
transport, and metabolism
FABP5 2171 fatty acid binding protein 5 intracellular protein involved in fatty acid uptake,
transport, and metabolism
Lysosome function
LIPA 3988 lysosomal acid lipase, lipase A, lysosomal enzyme involved in the hydrolysis of cholesteryl
esters and triglycerides
LAMP3 27074 LAMP, DC-LAMP, lysosomal- lysosomal function
associated membrane protein 3
Vol. 53, 2004 Human dendritic cell profiling 431

Table 2. (continued)

Locus Link Name Locus Link ID Additional names Description

Membrane protein
CD36 948 FAT, collagen type I receptor scavenger receptor for oxidized LDL, cell adhesion
CD44 960 H-CAM, hermes cell adhesion
CD53 963 MOX44 cell surface glycoprotein which interacts with integrins
CD58 965 lymphocyte function-associated immunoglobulin receptor family member involved in cell adhesion
antigen 3, LFA3
CD63 967 LAMP-3 cell surface glycoprotein which complexes with integrins
ITGAX 3687 CD11c, alpha x integrin, CR4, cell adhesion
leukocyte surface antigen p150
ITGB2 3689 CD18; integrin, beta 2 cell adhesion
ITGB5 3693 integrin, beta 2 cell adhesion
MRC1 4360 mannose receptor C type 1, membrane receptor involved in endocytosis
macrophage mannose receptor
SPN 6693 CD43, sialophorin cell adhesion, possibly role in T cell activation
Membrane receptors
FCER1 2208 CD23, FCeRII immunoglobulin (IgE) receptor
FCGR2A 2212 CD32; FcgRIIa receptor immunoglobulin (IgG) receptor
FCGR23A 2214 CD16; FcgRIIIa receptor immunoglobulin (IgG) receptor
IFNGR1 3459 CD119. Interferon gamma receptor ligand binding chain of interferon gamma receptor
IFNGR2 3460 interferon gamma receptor 2 beta chain of interferon gamma receptor
IL4R 3566 CD124, interleukin 4 receptor, subunit for formation of high affinity IL-4 and IL-13 receptors
alpha chain
Metabolism
ALOX15 246 arachidonate 15-lipoxygenase enzyme involved in the production of bioactive lipid molecules
CAT 847 Catalase antioxidant enzyme, converting H2O2 to H2O
GLUD1 2746 glutamate dehydrogenase 1 involved in the synthesis and catabolism of glutamate
ITPKB 3707 Inositol-trisphosphate 3-kinase B, IP3 kinase which phosphorylates inositol 1,4,5 triphosphate to
inositol 1,3,4,5 P4
LPL 4023 lipoprotein lipase, LIPD functions as a triglyceride hydrolase and associated with
receptor-mediated lipoprotein uptake
MAOA 4128 Monoamine oxidase A mitochondrial protein which degrades amine neurotransmitters
such as dopamine and serotonin
PCBD 5092 Pterin-4a-carbinolamine enzyme involved in phenylalanine hydroxylation
dehydratase, PCD
MGLL 11343 monoglyceride lipase lipid metabolism
Miscellaneous
A2M 2 a2-macroglobulin protease inhibitor, cytokine transporter
ECM1 1893 extracellular matrix protein 1 extracellular matrix protein
F13A1 2162 factor XIIIa, coagulation factor XIII, transglutaminase involved in the gamma-glutamyl-epsilon-
a1 polypeptide lysine crosslinking of fibrin molecules for coagulation
SERPINB6 5269 protease inhibitor 6 serine protease inhibitor
RNASE1 6035 RNAse A, family 1 (pancreatic) secretory ribonuclease
SPP1 6696 osteopontin, OPN, BNSP extracellular matrix protein
KIAA0100 9703 function unknown
KIAA0193 9805 secernin 1 cytosolic protein involved in secretion
SPINT2 10653 placental bikunin, HAI2, hepatocyte serine protease inhibitor
growth factor activator inhibitor type 2
DIPA 11007 Hepatitis delta antigen interacting modulates hepatitis virus delta replication
protein A
KIAA0179 23076 function unknown
432 Z. Tang and A. Saltzman Inflamm. res.

Table 2. (continued)

Locus Link Name Locus Link ID Additional names Description

Nuclear proteins/replication/translation
SNRPN 6638 small nuclear ribonucleoprotein pre-mRNA processing
polypeptide N
HMGN3 9324 TRIP7 modulates chromatin structure to enhance transcriptional activity
BRRN1 23397 KIAA0074, barren homolog DNA replication
(drosophila), HCAP-H
Protein chaperone
HSPB1 3315 HSP27, HSP28, hsp25, heat shock stress response protein
27 protein 1
Secreted proteases/cell migration
ADAM8 101 CD156 cell surface metalloproteinase
C1QB 713 complement C1q B chain component of serum complement system
MMP12 4321 macrophage metalloelastase, HME extracellular matrix degradation
T cell activation
CD86 942 CD28 antigen ligand 2, B7-2 immunoglobulin superfamily member which is a costimulatory
molecule for T cell activation
CD83 9308 immunoglobulin superfamily member important in dendritic
cell activation of T cells
Transcription factor
AES 166 amino-terminal enhancer of split transcription co-repressor
CEBPA 1050 CEBP transcription factor
CITED2 10370 MRG1 Cbp/p300-interacting transcription transactivator
Vesicular movement/cytoskeleton reorganization
ARHA 387 ras homolog gene family, member A; GTPase involved in cytoskeletal reorganization
RHOA
IGF2R 3482 CD222, IGF-2 receptor, insulin-like involved in sorting lysosomal enzymes to lysosomes
growth factor receptor 2
VIM 7431 vimentin intermediate filament protein
VAMP8 8673 vesicle-associated membrane protein 8 membrane protein involved in vesicle trafficking
(endobrevin)
TMSB10 9168 thymosin beta-10 involved in actin filament assembly
ARPC2 10109 actin related protein 2/3 complex, subunit of arp2/3 complex which is involved in actin
subunit 2, 34 kDa; ARC34 polymerization

Table 3. Upregulated genes identified in multiple profiling .studies in dendritic cells upon LPS treatment.

Locus Link Name Locus Link ID Additional names Description

Antigen presentation/processing
HLA-A 3105 major histocompatability complex, MHC I component
class I, A
PSMA3 5684 proteasome (prosome, macropain) proteasome subunit, member of peptidase T1A family
subunit, alpha type, 3; HC8
PSMB8 5696 proteasome subunit, beta type 8; proteasome component
RING10; LMP7
PSMB10 5699 proteasome subunit, beta type, 10 proteasome subunit
PSME1 5720 proteasome (prosome, macropain) proteasome subunit
activator subunit 1 (PA28 alpha)
TAP1 6890 transporter 1, ATP-binding cassette, transporter involved in transporting peptides across ER
sub-family B (MDR/TAP), RING4 for MHC I peptide loading
Cell signaling
DUSP1 1843 dual-specificity phosphatase 1 serine/threonine phosphatase which can inactivate MAP kinase
DUSP2 1844 dual-specificity phosphatase 2 serine/threonine phosphatase which can inactivate MAP kinase
DUSP5 1847 dual-specificity phosphatase 5 serine/threonine phosphatase which can inactivate MAP kinase
LYN 4067 v-yes-1 Yamaguchi sarcoma viral tyrosine kinase associated with receptor signaling,
related oncogene homolog such as immunoglobulin receptors
Vol. 53, 2004 Human dendritic cell profiling 433

Table 3. (continued)

Locus Link Name Locus Link ID Additional names Description

RGS1 5996 regulator of G-protein signaling 1, IER1 negative regulator of G-protein coupled receptor signaling
TRAF1 7185 TNF receptor-associated factor 1 mediates signal transduction from TNF receptor
superfamily members
TANK 10010 I-TRAF sequester and inhibitor of TRAF function
TNIP1 10318 NAF1, TNFAIP3 interacting protein which attenuates NFkB and ERK2 signaling
protein 1, ABIN-1
Cell survival/apoptosis/proliferation
BIRC3 330 MIHC, CIAP2, AIP1 inhibitor of apoptosis
BCL2A1 597 BCL2-related protein A1 anti-apoptotic protein
CASP7 840 caspase 7, MHC3 cysteine protease which induces apoptosis
GADD45A 1647 growth arrest and DNA-damage- stress induced protein involved in growth suppression
inducible, alpha; DDIT1, GADD45
MCL1 4170 myeloid cell leukemia sequence 1 BCL-2 family member which is both anti- and pro- apoptotic
depending on isoform produced
BTG2 7832 B-cell translocation gene 2, PC3, TIS21 protein involved in regulation of G1/S transition in cell cycle
TAX1BP1 8887 Tax1 binding protein, T6BP, TXBP151 antiapoptotic protein
Chemokines
CXCL1 2919 GRO1, GRO alpha, SCYB1 neutrophil chemoattractant
CXCL2 2920 GRO2, GRO beta, MIP2, SCYB2 neutrophil chemoattractant
CXCL3 2921 GRO3, GRO gamma, MIP2B, SCYB3 neutrophil chemoattractant
IL8 3576 interleukin 8, SCYB8 neutrophil and T cell chemoattractant
CXCL9 4283 MIG, HUMIG, SCYB9 T cell chemoattractant
CCL4 6351 MIP1B, LAG1, SCYA4 immunocyte chemoattractant
CCL5 6352 RANTES, SCYA5 chemoattractant for memory T cells, monocytes, and eosinophils
CCL8 6355 MCP2, SCYA8, SCYA10 immunocyte chemoattractant
CCL17 6361 TARC, SCYA17 T cell chemoattractant
CCL19 6363 ELC, MIP3b, SCYA19 B cell, T cell, and dendritic cell chemoattractant
CCL22 6367 MDC, SCYA22, STCP-1 NK cell, activated T cell, and dendritic cell chemoattractant
CXCL11 6373 ITAC, IP9, SCYB11, SCYB9B T cell chemoattractant
Cytokines/hormones
IGFBP4 3487 insulin-like growth factor binding protein which interacts with insulin like growth factor
protein 4; IBP4
IL1B 3553 interleukin 1, beta inflammatory cytokine
IL1RN 3557 interleukin 1 receptor antagonist, IL1RA antagonist for interleukin 1 receptor
IL6 3569 interleukin 6; interferon, beta 2 inflammatory cytokine
INHBA 3624 inhibin, beta A; RDF, FRP hormone and growth/differentiation factor
TGFA 7039 transforming growth factor, alpha inflammatory cytokine
PBEF 10135 pre-B-cell colony-enhancing factor B cell cytokine
Membrane protein
CD33 945 p67, SIGLEC-3 sialic acid recognizing cell surface lectin
SLC31A2 1318 solute carrier family 31 (copper copper transporter
transporters), member 2; CTR2
ICAM1 3383 CD54 adhesion molecule
MRC1 4360 mannose receptor C type 1, membrane receptor involved in endocytosis
macrophage mannose receptor
NINJ1 4814 ninjurin 1 adhesion molecule
Membrane receptors
ADORA3 140 adenosine A3 receptor G-protein coupled receptor
CD97 976 TM7LN1 seven transmembrane protein with EGF-like modules that
binds to CD55 (decay accelerating factor)
CCR7 1236 EBI1, chemokine receptor 7 chemokine receptor which binds CCL19
IL4R 3566 CD124, interleukin 4 receptor, subunit for formation of high affinity IL-4 and IL-13 receptors
alpha chain
IL7R 3575 interleukin 7receptor cytokine receptor
434 Z. Tang and A. Saltzman Inflamm. res.

Table 3. (continued)

Locus Link Name Locus Link ID Additional names Description

IL13RA1 3597 interleukin receptor 13, alpha 1 primary binding subunit of IL13 receptor and possibly a
IL4 receptor subunit
IL15RA 3601 Interleukin 15 receptor, alpha cytokine receptor
LY64 4064 lymphocyte antigen-64, CD180; RP105 pathogen receptor with structural similarities to Toll-like receptor 4
PTGER4 5734 prostaglandin E receptor 4, EP4 G-protein coupled receptor
CXCR4 7852 NPY3R, fusin, neuropeptide Y chemokine receptor for SDF-1
receptor Y3
TNFSF10 8743 APO2L, TRAIL TNF ligand superfamily member which induces cell apoptosis
CCRL2 9034 CRAM-A, CRAM-B, CKRX chemokine receptor
Metabolism
GK 2710 glycerol kinase enzyme involved in glycerol metabolism
INDO 3620 indoleamine-pyrrole 2,3 enzyme which catalyzes the degradation of L-tryptophan
dioxygenase; IDO to N-formylkynurenine
LDHA 3939 lactate dehydrogenase A, LDH1 glycolysis enzyme involved in the conversion of L-lactate
and NAD to pyruvate and NADH
MT1E 4493 metallothionein 1E protein which binds heavy metals
MT1G 4495 metallothionein 1G protein which binds heavy metals
MT1H 4496 metallothionein 1H protein which binds heavy metals
MT1X 4501 metallothionein 1X protein which binds heavy metals
MT2A 4502 metallothionein 2A protein which binds heavy metals
NCF1 4687 neutrophil cytosolic factor 1, subunit of NADPH oxidase
NOXO2, p47phox
OAS2 4939 2¢-5¢-oligoadenylate synthetase catalyzes the 2¢,5¢ oligomers of adenosine to activate RNase L
2, 69/71kDa
PGK1 5230 phosphoglycerate kinase 1 glycolysis enzyme catalyzing 1,3-diphosphoglycerate to
3-phosphoglycerate
SAT 6303 spermidine/spermine N1- rate limiting enzyme in the catabolic pathway of
acetyltransferase polyamine metabolism
SOD2 6648 superoxide dismutase 2, mitochondrial manganese superoxide dismutase
TXN 7295 thioredoxin oxidoreductase enzyme
YWHAQ 10971 tyrosine 3/tryptophan 5-monooxygenase potentially associated with regulation of monoamine biosynthesis
activation protein, theta polypeptide;
1C5; HS1; 14-3-3 protein tau
Miscellaneous
BST2 684 bone marrow stromal cell antigen 2 function unknown
BTG1 694 B-cell translocation protein 1 function unknown
IFI35 3430 interferon-induced protein 35, IFP35 function unknown
IFIT4 3437 interferon-induced protein with function unknown
tetratricopeptide repeats 4, CIG-49
LGALS3BP 3959 lectin, galactoside-binding, soluble, binds macrophage-associated lectin, MAC-2, and galectin 1,
3 binding protein; MAC-2-BP a beta-galactoside binding protein
LGALS9 3965 lectin, galactoside-binding, soluble, beta-galactoside binding protein implicated in modulating
9; galectin 9; ecalectin cell-cell and cell-matrix interactions
MX2 4600 myxovirus (influenza virus) member of dynamin family and large GTPase family which
resistance 2, MXB exists as a nuclear form and a cytoplasmic form
QSCN6 5768 quiescin Q6 function unknown
RCN1 5954 reticulocalbin calcium binding protein located in lumen of ER
S100A9 6280 S100 calcium-binding protein A9, member of S100 family of calcium binding proteins
calgranulin B, MIF, NIF, P14, CAGB,
CFAG, CGLB, L1AG, MRP14
TNFAIP2 7127 tumor necrosis factor-alpha induced function unknown
protein 2, B94 protein
PHLDA2 7262 pleckstrin homology-like domain, function unknown
family A, member 2, IPL, TSSC3
Vol. 53, 2004 Human dendritic cell profiling 435

Table 3. (continued)

Locus Link Name Locus Link ID Additional names Description

WNT5A 7474 wingless-type MMTV integration site secreted signaling protein involved in differentiation
family, member 5A
GIP2 9636 interferon, alpha inducible protein ubiquitin homolog
(clone IFI-15K), ISG15
MRF-1 10865 modulator recognition factor I function unknown
TIP-1 30851 Tax interaction protein 1 function unknown
Nuclear proteins/replication/translation
MX1 4599 myxovirus (influenza virus) resist- nuclear member of dynamin family and large GTPase family
ance 1, interferon-inducible protein
p78
PPP1R7 5510 protein phosphatase 1, regulatory regulatory subunit of serine/threonine phosphatase
subunit 7; SDS22 potentially involved in mitosis
WARS 7453 tryptophanyl tRNA synthetase enzyme which catalyzes the aminoacylation of tRNA (trp)
with tryptophan
PTP4A1 7803 protein tyrosine phosphatase type IVA, tyrosine phosphatase which is a nuclear protein but may also
member 1; PRL1 be associated with the plasma membrane
SUI1 10209 A121, ISO1 translation initiation factor
Protein chaperone
HSPA1A 3303 heat shock 70kDa protein 1A, molecular chaperone protein
HSP70-1A
HSPA4 3308 heat shock 70kDa protein 4, RY, molecular chaperone protein
APG-2, hsp70
HSPB1 3315 heat shock 27kDa protein 1, HSP27, molecular chaperone protein
HSP28, Hsp25
Secreted proteases/cell migration
BF 629 B-factor, properdin, complement factor complement protein
B preproprotein
MMP1 4312 matrix metalloproteinase 1, secreted proteinase which digests interstitial collagens type I,
interstitial collagenase II, and III
MMP9 4318 matrix metalloproteinase 9, gelatinase B secreted protease which degrades type IV and V collagen
MMP12 4321 macrophage metalloelastase, HME extracellular matrix degradation
MMP19 4327 matrix metalloproteinase 19; MMP18; matrix metalloproteinase whose function is unknown
RASI-1
TNFAIP6 7130 tumor necrosis factor-alpha induced secretory protein with hyaluronan-binding domain, a domain
protein 6, TSG6 associated with extracellular matrix stability and cell migration
T cell activation
CD86 942 CD28 antigen ligand 2, B7-2 immunoglobulin superfamily member which is a costimulatory
molecule for T cell activation
SLAMF1 6504 SLAM, CDw150 immunoglobulin superfamily member involved in T cell and
B cell stimulation
CD83 9308 immunoglobulin superfamily member important in dendritic
cell activation of T cells
Transcription factor
RUNX3 864 runt-related transcription factor 3, transcription factor
AML2, CBFA3
IRF1 3659 interferon regulatory factor 1, MAR transcription factor which activates interferons alpha and
beta transcription
IRF2 3660 interferon regulatory factor 2 competitively inhibits IRF1 mediated activation of interferons
alpha and beta transcription
IRF4 3662 interferon regulatory factor 4, MUM1 transcription factor involved in B cell development
IRF7 3665 interferon regulatory factor 7 transcription factor which activates interferon beta transcription
LYL1 4066 lymphoblastic leukemia derived Potentially involved in transcriptional regulation
sequence 1
NFE2L2 4780 nuclear factor (erythroid-derived 2)- transcription factor involved in antioxidant response
like 2, NRF2
436 Z. Tang and A. Saltzman Inflamm. res.

Table 3. (continued)

Locus Link Name Locus Link ID Additional names Description

NFKB2 4791 nuclear factor of kappa light poly- transcription factor NfkB subunit
peptide gene enhancer in B-cells 2
(p49/p100), LYT10
NFKBIA 4792 MAD-3, IKBA, I kappa B alpha inhibitory subunit of NFkB
STAT1 6772 signal transducer and activator of transcription factor phosphorylated and activated in cells in
transcription 1 response to cytokines and growth factors
STAT4 6775 signal transducer and activator of transcription factor phosphorylated and activated in cells in
transcription 4 response to cytokines and growth factors
STAT5A 6776 signal transducer and activator of transcription factor phosphorylated and activated in cells in
transcription 5A response to cytokines and growth factors
VDR 7421 vitamin D (1,25-dihydroxyvitamin steroid hormone receptor superfamily member
D3) receptor
NMI 9111 N-myc and STAT interactor augments STAT mediated transcription
ISGF3G 10379 interferon-stimulated transcription transcription factor which stimulates transcription of interferon
factor 3, gamma (48kD); p48; alpha inducible genes
IRF9; ISGF3
PNRC1 10957 PROL2, B4-2, PRR2 nuclear receptor coactivator
Vesicular movement/cytoskeleton reorganization
DAB2 1601 disabled homolog 2, mitogen- protein potentially involved in exocytosis
responsive phosphoprotein
(Drosophila); DOC2
PLEK 5341 pleckstrin, p47 protein kinase C substrate associated with phagosomal membranes
FSCN1 6624 SNL, fascin homolog 1, fascin 1 putative actin bundling factor
TRIP10 9322 thyroid hormone receptor interactor 10 possible regulation of actin cytoskeleton
CKAP4 10970 cytoskeleton-associated protein 4, microtubule binding protein located in the endoplasmic reticulum
p63, CLIMP-63
MLP 65108 macmarcks, MARCKS-like protein protein kinase C substrate potentially involved in cytoskeletal
organization

Table 4. Upregulated genes identified in multiple profiling .studies in dendritic cells upon TNF-a treatment.

Locus Link Name Locus Link ID Additional names Description

Antigen presentation/processing
PSME2 5721 proteasome activator subunit 2, proteasome subunit
PA28beta
TAP1 6890 transporter 1, ATP-binding cassette, transporter involved in transporting peptides across ER for
sub-family B (MDR/TAP), RING4 MHC I peptide loading
Cell signaling
DUSP4 1846 dual specificity phosphatase 4, TYP, serine/threonine phosphatase which can inactivate MAP kinase
HVH2, MKP2, MKP-2
PRKAR2B 5577 protein kinase, cAMP-dependent, regulatory subunit for cAMP dependent protein kinase
regulatory, type II, beta; PRKAR2;
RII-BETA
TRAF1 7185 TNF receptor-associated factor 1 mediates signal transduction from TNF receptor superfamily
members
Cell survival/apoptosis/proliferation
BIRC3 330 MIHC, CIAP2, AIP1 inhibitor of apoptosis
MCM5 4174 minichromosome maintenance deficient protein potentially involved in cell cycle regulation
protein 5, CDC46 homolog, CDC46
STK4 6789 KRS2, MST1 serine/threonine kinase associated with apoptosis
Chemokines
IL8 3576 interleukin 8, SCYB8 neutrophil and T cell chemoattractant
CCL2 6347 HC11, MCAF, MCP1, MCP-1, SCYA2, immunocyte chemoattractant
GDCF-2
Vol. 53, 2004 Human dendritic cell profiling 437

Table 4. (continued)

Locus Link Name Locus Link ID Additional names Description

CCL5 6352 RANTES, SCYA5 chemoattractant for memory T cells, monocytes, and eosinophils
CCL8 6355 MCP2, SCYA8, SCYA10 immunocyte chemoattractant
CCL17 6361 TARC, SCYA17 T cell chemoattractant
Cytokines/hormones
IL6 3569 interleukin 6; interferon, beta 2 inflammatory cytokine
TGFA 7039 transforming growth factor, alpha inflammatory cytokine
Lysosome function
LAMP3 27074 LAMP, DC-LAMP, lysosomal- lysosomal function
associated membrane protein 3
Membrane protein
CD44 960 H-CAM, hermes cell adhesion
ICAM1 3383 CD54 adhesion molecule
PLAUR 5329 plasminogen activator, urokinase membrane protein involved in cell surface plasminogen
receptor; CD87; UPAR; URKR activation; potential role in cell adhesion
SLC3A2 6520 solute carrier family 3, member 2; neutral and positive charged amino acid transporter
4F2; CD98; MDU1; 4F2HC; NACAE
PSCDBP 9595 pleckstrin homology, Sec7 and coiled- potential involvement in cell adhesion
coil domains, binding protein; HE;
B3-1; CYBR
Membrane receptors
CD58 965 lymphocyte function-associated immunoglobulin receptor family member involved in cell adhesion
antigen 3, LFA3
CCR7 1236 EBI1, chemokine receptor 7 chemokine receptor which binds CCL19
FLT3 2322 fms-related tyrosine kinase 3, FLK2, growth factor receptor tyrosine kinase family member
STK1, CD135
IGF1R 3480 insulin-like growth factor 1 receptor growth factor receptor tyrosine kinase family member
IL4R 3566 CD124, interleukin 4 receptor, subunit for formation of high affinity IL-4 and IL-13 receptors
alpha chain
IL7R 3575 interleukin 7receptor cytokine receptor
IL15RA 3601 Interleukin 15 receptor, alpha cytokine receptor
TM7SF1 7107 transmembrane 7 superfamily G-protein coupled receptor
member 1 (upregulated in kidney)
CXCR4 7852 NPY3R, fusin, neuropeptide Y chemokine receptor for SDF-1
receptor Y3
TNFRSF11A 8792 tumor necrosis factor receptor super- TNF receptor superfamily member
family, member 11a, EOF, PDB2, RANK
Metabolism
ALOX15B 247 arachidonate 15-lipoxygenase, enzyme which catalyzes the oxygenation of arachidonic acid
second type at the 15S position
INDO 3620 indoleamine-pyrrole 2,3 dioxygenase; enzyme which catalyzes the degradation of L-tryptophan
IDO to N-formylkynurenine
PFKM 5312 phosphofructokinase, muscle glycolysis enzyme which converts fructose 6-phosphate to
fructose 1,6-bisphosphate
SOD2 6648 superoxide dismutase 2, mitochondrial manganese superoxide dismutase
MGLL 11343 monoglyceride lipase lipid metabolism
Miscellaneous
BTG1 694 B-cell translocation protein 1 function unknown
GRSF1 2926 G-rich RNA sequence binding factor 1 cellular protein which binds RNAs containing the G-rich element
LGALS9 3965 lectin, galactoside-binding, soluble, 9; beta-galactoside binding protein implicated in modulating
galectin 9; ecalectin cell-cell and cell-matrix interactions
TGM2 7052 transglutaminase 2 (C polypeptide, enzyme involved in the crosslinking of proteins by epsilon-
protein-glutamine-gamma-glutamyl- gamma glutamyl lysine isopeptide bonds
transferase); TGC
TNFAIP2 7127 tumor necrosis factor-alpha induced function unknown
protein 2, B94 protein
438 Z. Tang and A. Saltzman Inflamm. res.

Table 4. (continued)

Locus Link Name Locus Link ID Additional names Description

TNFAIP6 7130 tumor necrosis factor-alpha induced secretory protein with hyaluronan-binding domain, a domain
protein 6, TSG6 associated with extracellular matrix stability and cell migration
OPTN 10133 optineurin, NRP, FIP2, HIP7, HYPL, protein which interacts with adenovirus E3 14.7K protein and
GLC1E, TFIIIA-INTP transcription factor IIIA
FLN29 10906 function unknown
MMD 23531 monocyte to macrophage differen- function unknown
tiation-associated, MMA
Nuclear proteins/replication/translation
NBS1 4683 nibrin, p95 protein of the MRE11/ protein believed to be involved in DNA double-strand break
RAD50 complex, ATV, NBS, AT-V1, repair and DNA damage-induced checkpoint activation
AT-V2
Protein chaperone
SIAH2 6478 seven in absentia homolog 2 regulator of protein stability
T cell activation
SLAMF1 6504 SLAM, CDw150 immunoglobulin superfamily member involved in T cell and
B cell stimulation
CD83 9308 immunoglobulin superfamily member important in dendritic
cell activation of T cells
Transcription factor
FOXO1A 2308 forkhead box O1A, FKH1, FKHR, transcription factor
FOXO1
ID2 3398 inhibitor of DNA binding 2, IDA2 transcriptional regulator
IRF4 3662 interferon regulatory factor 4, MUM1 transcription factor involved in B cell development
NFKBIA 4792 MAD-3, IKBA, I kappa B alpha inhibitory subunit of NFkB
NFKBIE 4794 nuclear factor of kappa light poly- inhibitory subunit of NFkB
peptide gene enhancer in B-cells
inhibitor, epsilon; IKBE
RELB 5791 nuclear factor of kappa light polypep- transcription factor NfkB subunit
tide gene enhancer in B-cells 3, I-REL
REL 5966 transcription factor, component of NF-kB
STAT5A 6776 signal transducer and activator of transcription factor phosphorylated and activated in cells
transcription 5A in response to cytokines and growth factors
TNFAIP3 7128 tumor necrosis factor, alpha-induced zinc finger protein which inhibits NfkB activation and
protein 3; A20; TNFA1P2 TNF induced apoptosis
NR4A3 8013 nuclear receptor subfamily 4, group A, steroid hormone receptor superfamily member
member 3; CHN; TEC; CSMF; NOR1;
MINOR
Vesicular movement/cytoskeleton reorganization
KIF2 3796 kinesin heavy chain member 2, HK2 microtubule associated motor protein
LAD1 3898 ladinin 1, LADA potential anchoring filament that is component of
basement membranes
LAMB3 3914 laminin, beta 3; LAMNB1; subunit of laminin, a family of basement membrane proteins
MARCKS 4082 myristoylated alanine-rich protein actin filament crosslinking protein
kinase C substrate, phosphomyristin,
MACS, PKCSL
Vol. 53, 2004 Human dendritic cell profiling 439

Table 5. Upregulated genes identified in multiple profiling .studies in dendritic cells upon CD40L treatment.

Locus Link Name Locus Link ID Additional names Description

Antigen presentation/processing
B2M 567 beta-2-microglobulin component of MHC1 complex
Cell survival/apoptosis/proliferation
BIRC3 330 MIHC, CIAP2, AIP1 Inhibitor of apoptosis
CCNG2 901 cyclin G2 regulation of cell cycle
Chemokines
IL8 3576 interleukin 8, SCYB8 neutrophil and T cell chemoattractant
CXCL9 4283 MIG, HUMIG, SCYB9 T cell chemoattractant
CCL17 6361 TARC, SCYA17 T cell chemoattractant
CCL20 6364 MIP-3a, LARC, SCYA20 lymphocyte chemoattractant
Cytokines/hormones
IL1B 3553 interleukin 1, beta inflammatory cytokine
Membrane receptors
CCR7 1236 EBI1, chemokine receptor 7 chemokine receptor which binds CCL19
Protein chaperone
HSPCA 3320 heat shock 90kD protein 1, alpha; hsp90 molecular chaperone protein
T cell activation
SLAMF1 6504 SLAM, CDw150 immunoglobulin superfamily member involved in T cell and
B cell stimulation
CD83 9308 immunoglobulin superfamily member important in dendritic
cell activation of T cells
Transcription factor
IRF1 3659 interferon regulatory factor 1, MAR transcription factor which activates interferons alpha and
beta transcription
REL 5966 transcription factor, component of NF-kB
Vesicular movement/cytoskeleton reorganization
CHS1 1130 Chediak-Higashi syndrome 1, beige lysosomal trafficking regulator
protein, CHS

ber of techniques using viral transduction methods have been Conclusion


published to introduce genes into dendritic cells for valida-
tion purposes, such as the introduction into dendritic cells of The accumulation of data being generated these past couple
dominant-negative forms of NFκB inducing kinase and IκB of years from profiling the expression of proteins and genes
kinase 2 [55] and p27KIP1 [56]. in human dendritic cells have yielded a wealth of exciting
There are potential issues with using the overexpression information. However, a number of challenges need to be
of proteins to validate the role of the protein in dendritic faced in the future. First, as our abilities to identify and iso-
cells. One caveat with the viral transduction methods is late dendritic cells produced in vivo improves; we need to
that the effects the process itself has on the function of the focus on profiling the genes and proteins expressed in these
dendritic cell needs to be closely monitored. Another issue cells. This capability will be also enhanced with the improve-
is that overexpressing a protein or a dominant negative form ments of methods to perform profiling experiments with less
of the protein may not be a feasible method for validating RNA, and subsequently less cells. Such studies are initiating
the function of certain types of proteins, for example pro- with profiling studies beginning to be published from in vivo
teases. In these cases, a method for the knockdown of the produced plasmacytoid cells and the preparation of Langer-
expression of a protein in a cell would be more appropriate. hans cells differentiated in vitro. Although the information
With the advent of siRNA technology, such an approach generated using monocyte derived dendritic cells has greatly
is beginning to be utilized in dendritic cells to reduce the increased our understanding of dendritic cell biology, greater
expression of a protein to determine its role in the cell relevance will come from studying the cells that actually
[57, 58]. For example siRNA technology was used by exist in vivo.
Laderach et al. (2003) in showing the importance of the p50 Secondly, as data from profiling experiments continues to
subunit of NF-κB for the CD40L/IL-1 mediated induction be generated, the next challenge will be to be able to effi-
of IL-12 production in human monocyte derived dendritic ciently utilize this information in experiments to determine
cells [57]. Such approaches will become more significant in the role of the respective protein or pathway has in dendritic
the future as we go beyond the profiling experiments to cell function. This will involve using techniques, such as ade-
determine the role the identified genes have in dendritic cell noviral transduction, to efficiently introduce genes into den-
function. dritic cells to modulate the levels of the respective protein or
440 Z. Tang and A. Saltzman Inflamm. res.

to introduce dominant negative forms of the protein to inhib- derived dendritic cells. Biochem Biophys Res Commun 2001;
it its function. In addition, the advent of siRNA technology 289: 531–8.
establishes a possibility to determine the role of proteins in [16] Lapteva N, Nieda M, Ando Y, Ide K, Hatta-Ohashi Y, Dymshits G,
et al. Expression of renin-angiotensin system genes in immature
cells where overexpression or the use of dominant negatives and mature dendritic cells identified using human cDNA microar-
are not feasible, such as in determining the role of proteases ray. Biochem Biophys Res Commun 2001; 285: 1059–65.
in dendritic cell function. [17] Le Naour F, Hohenkirk L, Grolleau A, Misek DE, Lescure P,
In summary, a great deal of knowledge has been generat- Geiger JD, et al. Profiling changes in gene expression during dif-
ed through profiling experiments that have increased our ferentiation and maturation of monocyte-derived dendritic cells
understanding of the biology of dendritic cells. This infor- using both oligonucleotide microarrays and proteomics. Proc Natl
Acad Sci USA 2001; 276: 17920–31.
mation will only increase as more sophisticated methods are [18] Moschella F, Maffei A, Cantanzaro RP, Papadopoulos KP, Skerrett
used to isolate rare types of dendritic cells for profiling D, Hesdorffer CS, et al. Transcript profiling of human dendritic
experiments. Such data presently existing and being generat- cells maturation-induced under defined culture conditions: com-
ed in the future will be form the basis of experiments to parison of the effects of tumour necrosis factor alpha, soluble
uncover the role of particular proteins or pathways in these CD40 ligand trimer and interferon gamma. Br J Haematol 2001;
cells. 114: 444–57.
[19] Ahn JH, Lee Y, Jeon CJ, Lee S-J, Lee B-H, Choi KD, et al. Identi-
fication of the genes differentially expressed in human dendritic
cell subsets by cDNA subtraction and microarray analysis. Blood
References 2002; 100: 1742–54.
[20] Lapteva N, Ide K, Nieda M, Ando Y, Hatta-Ohashi Y, Minami M,
[1] Banchereau J, Steinman RM. Dendritic cells and the control of et al. Activation and suppression of reonin-angiotensin system in
immunity. Nature 1999; 392: 245–52. human dendritic cells. Biochem Biophys Res Commun 2002; 296:
[2] Steinman RM. Dendritic cells. In: Paul WE, editor. Fundamental 194–200.
Immunology, Fourth Edition. Philadelphia:Lippincott-Raven, [21] Lindstedt M., Johansson-Lindbom B, Borrebaeck CAK. Global
1999: 547–73. reprogramming of dendritic cells in response to a concerted action
[3] Lambrecht BN, Hammad H. Taking our breath away: dendritic of inflammatory mediators. Int Immunol 2002; 14: 1203–13.
cells in the pathogenesis of asthma. Nat Rev Immunol 2003; 3: [22] Matsunga T, Ishida T, Takekawa M, Nishimura S, Adachi M, Imai
994–1003. K. Analysis of gene expression during maturation of immature
[4] Pettit AR, Thomas R. Dendritic cells: the driving force behind dendritic cells derived from peripheral blood monocytes. Scand J
autoimmunity in rheumatoid arthritis? Immunol Cell Biol 1999; Immunol 2002; 56: 593–601.
77: 420–7. [23] Rissoan M-C, Duhen T, Bridon J-M, Vermare NB, Péronne C, Vis
[5] Pascual V, Banchereau J, Palucka AK. The central role of dendrit- BDS, et al. Subtractive hybridization reveals the expression of
ic cells and interferon-alpha in SLE. Curr Opin Rheumatol 2003; immunoglobulinlike transcript 7, Eph-B1, granzyme B, and 3 nov-
15: 458–56. el transcripts in human plasmacytoid dendritic cells. Blood 2002;
[6] Link H, Huang Y-M, Xiao B-G. Dendritic cells in experimental 100: 3295–303.
allergic encephalomyelitis and multiple sclerosis. J Neuroim- [24] Schlaak JF, Hilkens CMU, Costa-Pereira AP, Strobl B, Aberger F,
munol 199; 100: 102–10. Frischauf A-M, et al. Cell-type and donor specific transcriptional
[7] Hashimoto S-I, Suzuki T, Dong H-Y, Nagai S, Yamazaki N, Mat- responses to interferon-α. J Biol Chem 2002; 277: 49428–37.
sushima K. Serial analysis of gene expression in human mono- [25] Chaussabel D, Semnani RT, McDowell MA, Sacks D, Sher A, Nut-
cyte-derived dendritic cells. Blood 1999; 94: 845–52. man TB Unique gene expression profiles of human macrophages
[8] Dietz AB, Bulur PA, Knutson GJ, Matasić R, Vuc-Pavlović S. and dendritic cells to phylogenetically distinct parasites. Blood
Maturation of human monocyte-derived dendritic cells studied by 2003; 102: 672–81.
microarray hybridization. Biochem Biophys Res Commun 2000; [26] Hashimoto S-I, Nagai S, Sese J, Suzuki T, Obata A, Sato T, et al.
275: 731–8. Gene expression profile in human leukocytes. Blood 2003; 101:
[9] Hashimoto S-I, Suzuki T, Nagai S, Yamashita T, Toyoda N, Mat- 3509–13.
sushima K. Identification of genes specifically expressed in [27] Izmailova E, Bertley FMN, Huang Q, Makori N, Miller CJ, Young
human activated and mature dendritic cells through serial analysis RA, et al. HIV-1 tat reprograms immature dendritic cells to
of gene expression. Blood 2000; 96: 2206–14. express chemoattractants for activated T cells and macrophages.
[10] Angénieux C, Fricker D, Strub J-M, Luche S, Bausinger H, Nat Med 2003; 9: 191–7.
Cazenave J-P, et al. Gene induction during differentiation of [28] Ju X-S, Hacker C, Madruga J, Kurz SM, Knespel S, Blendinger G,
human monocytes into dendritic cells: an integrated study at the et al. Towards determining the differentiation program of anti-
RNA and protein levels. Funct Integr Genomics 2001; 1: 323–9. gen – presenting cells by transcriptional profiling. Eur J Cell Biol
[11] Baltathakis J, Alcantara O, Boldt DH. Expression of different NF- 2003; 82: 75–86.
κB pathway genes in dendritic cells (DCs) or macrophages assessed [29] Messmer D, Messmer B, Chiorazzi N. The global transcriptional
by gene expression profiling. J Cell Biochem 2001; 83: 281–90. maturation program and stimuli-specific gene expression profiles
[12] Bleharski JR, Niazi KR, Sieling PA, Cheng G, Modlin, RL. Sig- of human myeloid dendritic cells. Int Immunol 2003; 15: 491–503.
naling lymphocytic activation molecule is expressed on CD40 lig- [30] Moschella F, Bisikirska B, Maffei A, Papadopoulos, KP, Skerrett,
and-activated dendritic cells and directly augments production of D, Liu Z, et al. Gene expression profiling and functional activity
inflammatory cytokines. J Immunol 2001; 167: 3174–81. of human dendritic cells induced with IFN-a-2b: implications for
[13] Huang Q, Liu D, Majewski P, Schulte LC, Korn JM, Young RA, et cancer immunotherapy. Clin Cancer Res 2003; 9: 2022–31.
al. The plasticity of dendritic cell responses to pathogens and their [31] Skelton L, Cooper M, Murphy M, Platt A. Human immature
components. Science 2001; 294: 870–5. monocyte-derived dendritic cells express the G protein-coupled
[14] Lapteva N, Ando Y, Nieda M, Hohjoh H, Okai M, Kikuchi A, et al. receptor GPR105 (KIAA001, P2Y14) and increase intracellular
Profiling of genes expressed in human monocytes and monocyte- calcium in response to its agonist uridine diphosphoglucose. J
derived dendritic cells using cDNA expression array. Br J Haema- Immunol 2003; 171: 1941–9.
tol 2001; 114: 191–7. [32] Türeci O, Bian H, Nestle FO, Raddrizzani L, Rosinski JA, Tassis
[15] Lapteva N, Nieda M, Ando Y, Nicol A, Ide K, Yamaura A, et al. A, et al. Cascades of transcriptional induction during dendritic cell
Gene expression analysis in human monocytes, monocyte-derived maturation revealed by genome-wide expression analysis. FASEB
dendritic cells, and a-galactosylceramide-pulsed monocyte- J 2003; 17: 836–47.
Vol. 53, 2004 Human dendritic cell profiling 441

[33] Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen [46] Jaksits S, Kriehuber E, Charbonnier AS, Rappersberger K, Stingl
by cultured human dendritic cells is maintained by granulocyte/ G, Maurer D. CD34+ cell-derived CD14+ precursor cells develop
macrophage colony-stimulating factor plus interleukin 4 and down- into langerhans cells in a TGF-β1-dependent manner. J Immunol
regulated by tumor necrosis factor α. J Exp Med 1994; 179: 1109–18 1999; 163: 4869–77.
[34] Bender A, Sapp M, Schuler G, Steinman RM, Bhardwaj N. [47] http://www.ncbi.nlm.nih.gov/LocusLink/
Improved methods for the generation of dendritic cells from non- [48] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
proliferating progenitors in human blood J Immunol Methods [49] Vincent MS, Gumperz JE, Brenner MB. Understanding the func-
1996;196:121-135. tion of CD1-restricted T cells. Nat Immunol 2003; 4: 517–23.
[35] Beutler B, Hoebe K, Du X, Ulevitch RJ. How we detect microbes [50] Vincent MS, Leslie DS, Gumperz JE, Xiong X, Grant EP, Brenner
and respond to them: Toll-like receptors and their transducers. J MB. CD1-dependent dendritic cell instruction. Nat Immunol
Leukoc Biol 2003; 74: 479–85. 2002; 3: 1163–8.
[36] Barton GM, Medzhitov R. Toll-like receptor signaling pathways. [51] Leslie DS, Vincent MS, Spada FM, Das H, Sugita M, Morita CT,
Science 2003; 300: 1524–5. et al. CD1-mediated γ/δ T cell maturation of dendritic cells. J Exp
[37] Gaur U, Aggarwal BB. Regulation of proliferation, survival, and Med 2002; 196: 1575–84.
apoptosis by members of the TNF superfamily. Biochem Pharma- [52] Vissers JLM, Hartgers FC, Lindhout E, Teunissen MBM, Figdor
col 2003; 66: 1403–8. CG, Adema GJ. Quantitative analysis of chemokine expression by
[38] Lam N, Sudgen B. CD40L and its viral mimic, LMP1: similar dendritic cell subsets in vitro and in vivo. J Leukoc Biol 2001; 69:
means to different ends. Cell Signal 2002; 15: 9–16. 785–93.
[39] Barton GM, Medzhitov R Linking Toll-like receptors to IFN-α/β [53] Bennouna S, Bliss SK, Curiel TJ, Denkers EY. Cross-talk in the
expression. Nat Immunol 2003; 4: 432–3. innate immune system:neutrophils recruitment and activation of
[40] Agrawal S, Agrawal A, Doughty B, Gerwitz A, Blenis J, Van Dyke dendritic cells during microbial infection. J Immunol 2003; 171:
T, et al. Different toll-like receptor agonists instruct dendritic cells 6052–8.
to induce distinct Th responses via differential modulation of [54] Schotte R, Rissoan M-C, Vermare N-B, Bridon J-M, Dihen T, Wei-
extracellular signal-regulated kinase-mitogen-activated protein jer K, et al. The transcription factor Spi-B is expressed in plasma-
kinase and c-fos. J Immunol 2003; 171: 4984–9. cytoid DC precursors and inhibits T-,B-, and NK-cell develop-
[41] Kohrgruber N, Halanek N, Gröger M, Winter D, Rappersberger K, ment. Blood 2003; 101: 1015–23.
Schmitt-Egenolf M, et al. Survival, maturation, and function of [55] Andreakos E, Smith C, Monaco C, Brennan FM, Foxwell BM,
CD11c- and CD11c+ peripheral blood dendritic cells are differen- Feldmann M. IκB kinase 2 but not NF-κB-inducing kinase is es-
tially regulated by cytokines. J Immunol 1999; 163: 3250–9. sential for efficient DC antigen presentation in the allogeneic
[42] Brière F, Bendriss-Vermare N, Delale T, Burg S, Corbet C, Rissoan mixed lymphocyte reaction. Blood 2003; 101: 983–91.
M-C, et al. Origin and filiation of human plasmacytoid dendritic [56] Woltman, AM, Van Der Kooij SW, Coffer PJ, Offringa R, Daha
cells. Hum Immunol 2003; 63: 1081–92. MR, Van Kooten C. Rapamycin specifically interferes with GM-
[43] Sigal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah CSF signaling in human dendritic cells, leading to apoptosis via
K, et al. The nature of the principal type 1 interferon-producing increased p27CIP expression. Blood 2003; 101: 1439–45.
cells in human blood. Science 1999; 284: 1835–7. [57] Laderach D, Compagno D, Danos O, Vainchenker W, Galy A. RNA
[44] Kadowski N, Ho S, Antonenko S, Malefyt RDW, Kastelein RA, interference shows critical requirement for NF-κB p50 in the pro-
Bazan F, et al. Subsets of human dendritic cell precursors express duction of IL-12 by human dendritic cells. J Immunol 2003; 171:
different toll-like receptors and respond to different microbial 1750–7.
antigens. J Exp Med 2001; 194: 863–9. [58] Hill JA, Ichim TE, Kusznieruk KP, Li M, Huang X, Yan X, et al.
[45] Jahnsen FL, Farkes L, Lund-Johansen F, Brandtzaeg P. Involve- Immune modulation by silencing IL-12 production in dendri-
ment of plasmacytoid dendritic cells in human disease. Hum tic cells using small interfering RNA. J Immunol 2003; 171:
Immunol 2002; 63: 1201–5. 691–6.