The Roles of Keratinocyte-Derived Cytokines in the Epidermis
and Their Possible Responses to UVA-Irradiation
Seiji Kondo
Department of Dermatology, Faculty of Medicine, Sapporo Medical University, Sapporo, Japan
Skin is the largest organ, covering the entire body surface.
Keratinocytes (KC) are its major component. The KC,
by making keratin protein, function as a protective
barrier against exogenous stimuli. As KC have been
demonstrated to produce various kinds of cytokines, skin
plays an important role in immunologic and inflammat-
ory responses of the body. Cytokines affect other cells
and organs, mediating cellular growth and differentiation
as well as inflammation and immune reactions. Thus,
cytokines maintain the cellular and intercellular homeost-
asis. Dysregulation and abnormal production of cytokines
are detected in various skin diseases. Evidence is accumu-
lating to show the significant contribution of cytokines
to the pathogenesis or severity of certain diseases. In this
report, the effects of KC-derived cytokines on various
K
eratinocytes (KC) are activated by environmental stimuli
to produce a variety of cytokines that can affect the
immune response as well as the cell growth and differen-
tiation of KC themselves and other cell components in
the skin in an autocrine, juxtacrine, or paracrine fashion.
There are several features distinguishing polypeptide hormones from
cytokines, such as the production from one type of specialized cells
versus more than one type of cell; uniqueness of action versus an
overlapping spectrum of actions (redundancy); restricted target cell
specificity and a limited spectrum of actions versus multiple target cells
and multiple actions (ambiguity); and an endocrine mode of action
versus autocrine, paracrine, or juxtacrine mode of action. Despite these
differences, however, because many properties are shared by these
polypeptides, it is not easy to differentiate cytokines from hormones.
Table I lists cytokines identified to be produced and released from
normal human KC under physiologic and pathophysiologic conditions.
We have recently shown that KC-derived cytokines such as IL-1α,
IL-6, and TNF-α are able to pass through the basement membrane,
and thus can affect components in the dermis as well as in the epidermis
where they reside (Kondo et al, 1997). In this paper, cytokines produced
by KC are summarized to introduce autocrine, juxtacrine, or paracrine
effects of KC-derived cytokines on KC, Langerhans cells, melanocytes,
fibroblasts, lymphocytes, mast cells, and vascular endothelial cells. Our
recent studies relevant to the role(s) of each cytokine in the skin are
also introduced.
Manuscript received April 27, 1999; accepted for publication June 15, 1999
Reprint requests to: Dr. Seiji Kondo, Department of Dermatology, Faculty
of Medicine, Sapporo Medical University, S1, W16, Chuo-ku, Sapporo 060–
8543, Japan. E-mail:seiji@sapmed.ac.jp
·
1087-0024/99/$14.00 Copyright © 1999 by The Society for Investigative Dermatology, Inc.
177
components in the skin are briefly summarized. We
further demonstrate that ultraviolet (UV) light has a
distinct effect on the production and secretion of cyto-
kines from KC, depending upon its wavelength. Although
some KC-derived cytokines were induced both by UVA
and by UVB, suggesting augmentative effects of UVA on
UVB-induced cutaneous responses such as sunburn and
suntan, other cytokines, including IL-10 and IL-12, were
found to be differentially regulated by UVA and UVB.
UVA (less than 20 kJ per m2) was found to induce IL-12
but not IL-10 in normal human KC. Our results suggest
an antagonistic effect of UVA against UVB, indicating
the contribution of UV irradiation to the balance between
Th1 and Th2 cytokines in the in situ skin. Key words:
knockout mice/transgenic mice/UVA. Journal of Investigative
Dermatology Symposium Proceedings 4:177–183, 1999
AUTOCRINE, JUXTACRINE, OR PARACRINE EFFECTS OF
KC-DERIVED CYTOKINES (FIG 1)
Interleukin (IL)-1 has been found to stimulate the production of other
cytokines such as IL-1, IL-6, IL-8, granulocyte-macrophage colony
stimulating factor (GM-CSF), and transforming growth factor (TGF)-
α in human KC. Moreover, IL-1 increases prostaglandin E2 (PGE2)
production from KC (Pentland et al, 1987). Finally IL-1 stimulates
proliferation and induces chemotaxis of KC in an autocrine fashion
(Ristow, 1987). IL-6 and IL-8 are known to stimulate KC proliferation
and/or chemotaxis, which are required for wound healing (Grossman
et al, 1989; Michel et al, 1992); however, in IL-6 transgenic mice in
which IL-6 is expressed in the basal cells by a human keratin 14
promoter, this does not lead to enhanced epidermal proliferation but
results in a thick stratum corneum (Turksen et al, 1992).
Tumor necrosis factor (TNF)-α is another proinflammatory cytokine
that induces several other cytokines but was found to suppress KC
proliferation (Symington, 1989). Like IL-1, TNF-α increases PGE2
production from KC and induces intercellular adhesion molecule
(ICAM)-1 expression on KC; however, what should be noted regarding
biologic effects caused by TNF-α is that different effects are observed
depending upon the concentration, the timing of its presence, and the
site of the body, as we have shown in a mouse model (Kondo and
Sauder, 1997). In TNF-α transgenic mice overexpression of TNF-α
from KC leads to cachexia, growth inhibition, graft versus host-disease
(GVHD)-like changes in the skin and intestine, and liver necrosis and
death (Cheng et al, 1992).
GM-CSF (Kaplan et al, 1992), TGF-α (Barrandon and Green, 1987),
amphiregulin (Cook et al, 1991), and nerve growth factor (NGF) (Di
Marco et al, 1991) have been shown to stimulate KC proliferation.
The role of TGF-α in epidermal growth and differentiation has been
described by the use of a TGF-α transgenic mouse model (Vassar and
Fuchs, 1991).
178 KONDO JID SYMPOSIUM PROCEEDINGS

Figure 1. Autocrine, juxtacrine, and paracrine effects of KC-derived

cytokines.

Figure 2. Effects of KC-derived cytokines on Langerhans cells.

TGF-β is known to exert a large variety of biologic functions in

Table I. Cytokines from human keratinocytes most cells. It suppresses KC growth (Matsumoto et al, 1990) but
simulates KC migration, which may be very important at sites of
KC-derived cytokines References
wound healing or other repair processes (Kane et al, 1991). TGF-β
Interleukines has been shown to induce IL-6 production from KC (Michel et al,
IL-1 Luger et al (1981) 1992). Modulation of integrins and their receptors by TGF-β has also
IL-6 Kirnbauer et al (1989) been demonstrated (Gailit et al, 1994); however, the importance of
IL-7 Heufler et al (1993) this cytokine in the epidermis as well as more complex actions in vivo
IL-8 Larsen et al (1989) were demonstrated in transgenic mice generated using either a keratin
IL-10 Enk et al (1995) 10 (Cui et al, 1995) or a keratin 1 promoter (Sellheyer et al, 1993)
controversial finding driving target expression of TGF-β1 in the suprabasal KC compartment.
reported by Teunissen et al The transgenic mice demonstrated that TGF-β1 could act as a regulator
(1997)
IL-12 Aragane et al (1994)
of both KC proliferation and turnover, to maintain homeostatic
Müller et al (1994) equilibrium within the epidermis.
IL-15 Mohamadzadeh et al (1995) It should be noted that KC do not produce epidermal growth factor
IL-18 (mouse) Stoll et al (1997) (EGF), keratinocyte growth factor (KGF), or hepatocyte growth factor
Tumor necrosis factors
(HGF), though they express receptors for these growth factors. It
TNF-α Köck et al (1990) should also be noted that KC do not express receptors for PDGF.
Colony-stimulating factors (CSF) EFFECTS OF KC-DERIVED CYTOKINES ON LANGERHANS
Granulocyte-macrophage (GM)-CSF Kapp et al (1987) CELLS (FIG 2)
Granulocyte-CSF (G-CSF) Denburg and Sauder (1986)
CSF-1 (macrophage-CSF) Chodakewitz et al (1990) The important role of KC-derived cytokines in immunologic reactions
Growth factors in skin is demonstrated by findings that they have significant effects
Transforming growth factor (TGF)-α Coffey et al (1987) on various aspects of Langerhans cells, though most studies have used
TGF-β Kane et al (1991) animals. Langerhans cells are considered a target for IL-1 activity in
leukemia inhibitory factor (LIF) Paglia et al (1996) the skin. It has been shown in murines that IL-1 acts on cultured
endothelin (ET)-1 Imokawa et al (1992) Langerhans cells, not only increasing their viability but also enhancing
amphiregulin Cook et al (1991) the functional activity of Langerhans cells (induction of MHC class II
platelet cell-derived growth factor (PDGF) Ansel et al (1993) molecule expression) when used together with GM-CSF to activate
basic fibroblast growth factor (bFGF) Halaban et al (1988) allogeneic T cells (Heufler et al, 1988). The viability of Langerhans
nerve growth factor (NGF) Di Marco et al (1991)
stem cell factor (SCF) Morita et al (1994)
cells is also sustained by IL-6 and GM-CSF. GM-CSF is also known
melanoma growth-stimulating activity Richmond et al (1989) to sustain the immunostimulatory capacity of Langerhans cells. IL-10
(MGSA) growth-related gene product (Gro) was originally described as a Th2-derived cytokine that inhibits the
vascular endothelial growth factor (VEGF) Ballaun et al (1995) cytokine release by Th1 cells stimulated in the presence of accessory
Interferons
cells (Howard and O’Garra, 1992). KC-derived IL-10 can inhibit the
IFN-α/β Fujisawa et al (1997) antigen-presenting function of Langerhans cells for Th1 cells and
decrease the expression of costimulatory molecules such as B7-1 and
Chemokines B7-2 (Kawamura and Furue, 1995). IL-10 knockout mice were
(a) C-X-C (α) chemokines
IL-8 Larsen et al (1989)
revealed to have exaggerated cutaneous reactions to exogenous stimuli
MGSA/Gro Richmond et al (1989) (Berg et al, 1995), confirming that endogenous KC-derived IL-10
epithelial neutrophil-activating protein-78 Gillitzer et al (1996) is an important homeostatic molecule that acts to prevent excess
(ENA-78) inflammatory damage in skin; however, failure to detect IL-10 from
γ-interferon-inducible protein-10 (IP-10) Kaplan et al (1987) human KC has been reported (Teunissen et al, 1997). This controversy
(b) C-C (β) chemokines is still under debate.
regulated on activation, normal T cell Li et al (1996) KC-derived TNF-α is believed to be important in skin immunologic
expressed and secreted (RANTES) and inflammatory reactions. TNF-α enhances cellular intergrity of
monocyte chemotactic protein (MCP)-1/ cultured Langerhans cells and maintains cell viability, although it does
macrophage chemotactic activation factor Barker et al (1991)
(MCAF)
not affect functional maturation of Langerhans cells (Koch et al, 1990).
TNF-α has also been shown to serve as a stimulus for the migration
VOL. 4, NO. 2 SEPTEMBER 1999
Figure 3. Effects of KC-derived cytokines on melanocytes.
of Langerhans cells from skin to lymph nodes (Cumberbatch and
Kimber, 1992). TNF-α seems to cause morphologic damage to
Langerhans cells and induces an inability to elicit normal delayed-type
hypersensitivity (Simon et al, 1991). From studies using TNF-receptor
type 1- and type 2-deficient mice, the effects of TNF-α were
demonstrated to be regulated by balance between the local concentra-
tion of TNF-α and the levels of expression of TNF receptors, which
may account for several controversial results observed with respect to
the effects of TNF-α (Kondo and Sauder, 1997). This will be discussed
in the following section.
IL-6 also plays a role in local control of Langerhans cell number
and function (Belsito et al, 1989). The crucial in vivo role of IL-6 in
immunity and inflammation is demonstrated by the impaired immune
and acute phase responses in IL-6 knockout mice (Kopf et al, 1994).
IL-15 has been shown to function as a maturation factor for human
Langerhans cells to enhance the immunostimulatory capacity of these
cells.1 A chemotactic effect of KC-derived monocyte chemotactic
protein (MCP)-1 on Langerhans cells has been reported using the
MCP-1 transgenic mouse model (Nakamura et al, 1995).
EFFECTS OF KC-DERIVED CYTOKINES ON
MELANOCYTES (FIG 3)
Melanocyte growth-promoting activity was found in basic fibroblast
growth factor (bFGF) (Halaban et al, 1988), melanoma growth-
stimulatory activity (MGSA)/Gro (Bordoni et al, 1990), endothelin-1
(ET-1) (Imokawa et al, 1992), and stem cell factor (SCF) (Grabbe et al,
1994). TGF-β, IL-1α, IL-6, TNF-α, and interferon (IFN)-β have
been shown to have an inhibitory effect on melanocyte proliferation.
These cytokines also suppress the activity of melanocyte tyrosinase,
which results in decreased melanin synthesis. Alpha melanocyte stimu-
lating hormone (α-MSH) is a melanotropin secreted predominantly
by the pituitary. KC were found to release biologically active α-MSH
(Köck et al, 1991), which stimulates melanocyte proliferation when
added to TPA-supplemented tissue culture media (Herlyn et al, 1988).
EFFECTS OF KC-DERIVED CYTOKINES ON
LYMPHOCYTES (FIG 4)
IL-1, TNF-α, IL-8, MCP-1, and Gro were found to stimulate T cell
migration. IL-1, IL-6, and TNF-α are known to activate T cells as a
costimulatory factor. IL-1 can also elicit indirect negative effects on T
cells by inducing prostaglandins, which suppress T cell proliferation.
B cell growth and differentiation are regulated by IL-1, IL-6, and
TNF-α. IL-10 inhibits Th1 cytokines and promotes the growth of B
1Jonuleit H, Kühn U, Müller G, Wölfl M, Lohmann S, Saloga J, Becker D,
Knop J, Enk AH: Accessory cell functions of epidermal Langerhans cells and
blood dendritic cells are enhanced by keratinocyte derived IL-15. J Invest
Dermatol 105:454, 1995 (abstr.)
KERATINOCYTE-DERIVED CYTOKINES 179
Figure 4. Effects of KC-derived cytokines on lymphocytes.
cells. IL-12 is capable of selectively inducing a Th1-type immune
response by promoting T cell proliferation. IL-7, which was recently
demonstrated to be released from KC (Heufler et al, 1993), is a growth
factor for precursor B lymphocytes and T lymphocytes, costimulates
the proliferation of normal T lymphocytes, and augments the growth
and generation of cytotoxic T lymphocytes as well as lymphokine-
activated killer (LAK) cells. IL-15, which has biologic effects similar
to those of IL-2, enhances the proliferation and activation of T
lymphocytes, cytotoxic T lymphocytes, and LAK cells, as well as
natural killer cells. IL-15 is also a crucial signal molecule for IFN-γ
production by natural killer cells (Carson et al, 1994)
TGF-β has an antiproliferative effect on lymphocytes (Kehrl et al,
1986a, b). TGF-β inhibits the proliferation of T lymphocytes, B
lymphocytes, natural killer cells, and LAK cells, thus contributing to
the immunosuppressive effect. In addition, TGF-β influences a variety
of differentiation-associated functions, for example, although it is a
murine study, in B cells, TGF-β switched B cells from IgG and IgM
to the IgA phenotype (Coffman et al, 1989).
Gamma-interferon-inducible protein (IP)-10 recruits T lymphocytes
and monocytes that elicit a host-mediated antitumor effect in vivo
(Luster and Leder, 1993).
EFFECTS OF KC-DERIVED CYTOKINES ON FIBROBLASTS
(FIG 5)
Platelet-derived growth factor (PDGF) has been found to stimulate
fibroblasts to secrete somatomedin C, which itself is mitogenic for
these cells, and thus PDGF could further amplify its mitogenic effect
(Paulsson et al, 1987). PDGF is also known to be chemotactic for
fibroblasts and activates mesenchymal cells to secrete both collagen and
collagenase, thus mediating processes such as wound healing and tissue
repair (Pierce et al, 1991).
TGF-β is one of the most potent agents that can accelerate wound-
healing processes (Mustoe et al, 1987). It is a potent chemoattractant
for macrophages and fibroblasts and causes their activation
(Postlethwaite et al, 1987; Wahl et al, 1987). It was also shown to
stimulate collagen and fibronectin production in a variety of fibroblastic
cell lines (Ignotz and Massagué, 1986; Roberts et al, 1986). Exogenous
TGF-β administration in vivo has been shown to result in increased
cell density, fibrosis, and angiogenesis (Roberts et al, 1986).
IL-1α and TNF-α regulate collagen and collagenase synthesis and
can increase as well as inhibit collagen production of fibroblasts
depending upon the experimental conditions employed. Under serum-
free conditions collagen synthesis was stimulated by these cytokines,
whereas in the presence of serum no stimulatory effect or even
inhibition was demonstrated (Elias et al, 1990). IL-1 increases the
proliferation of fibroblasts, and this mitogenic activity seems to be
mediated by PDGF. Moreover, IL-1 regulates fibrosis by increasing
the transcription of type I, III, and IV collagens. KC-derived IL-1,
180 KONDO
Figure 5. Effects of KC-derived cytokines on fibroblasts.
Figure 6. Effects of KC-derived cytokines on mast cells.
which can be released as a result of skin damage, appears to be involved
in wound healing.
EFFECTS OF KC-DERIVED CYTOKINES ON MAST CELLS
(FIG 6)
Within the skin, mast cells reside in greater abundance in the loose
subepidermal, perivascular, and periappendageal connective tissue. They
can also be found in the epidermis. Mast cells are the first line of
cellular immunologic defense because they are the only effector cells
that reside in the tissues. Due to their proximity to the epidermis, mast
cells may be affected by KC-derived cytokines. Few studies have,
however, been done with human mast cells. Growth-promoting effects
on mast cells are seen for IL-3, IL-6, IL-10, GM-CSF, NGF, and SCF
in rodents. In humans, none of these factors are effective except SCF
(c-kit ligand), which is known to support mast cell growth (Costa et al,
1996). As KC have recently been found to produce SCF (Morita et al,
1994), dermal mast cells may be affected by the KC-derived c-kit
ligand. IL-6 was also found to prolong the survival of human mast
JID SYMPOSIUM PROCEEDINGS
Figure 7. Effects of KC-derived cytokines on endothelial cells.
cells (Yanagida et al, 1995). So-called histamine-releasing factors or
release-enhancing factors include IL-1, IL-8, SCF, GM-CSF, and
neutrophil-activating peptide (NAP)2. By contrast, growth inhibitory
activity on murine mast cells was observed in TGF-β1 (Broide et al,
1989) and histamine release from rat mast cells is suppressed by IFN-
α and IFN-β (Swieter et al, 1989)
EFFECTS OF KC-DERIVED CYTOKINES ON
ENDOTHELIAL CELLS (FIG 7)
IL-1 and TNF are two major cytokines that induce a series of changes
promoting the inflammatory process. IL-1 and TNF have been found
to stimulate endothelial cells to produce endothelial leukocyte adhesion
molecule 1 (ELAM-1), now termed E-selectin, vascular cell adhesion
molecule 1 (VCAM-1), and ICAM-1 (Dustin et al, 1986). These
molecules differ in their specificity for leukocytes and in the timing of
their expression. The expression of ELAM-1 is induced by IL-1 and
TNF-α, peaks at 4–6 h, and mostly disappears by 24 h (Bevilacqua
et al, 1987). E-selectin binds to neutrophils, memory T lymphocytes,
eosinophils, and monocytes. VCAM-1 is the second endothelial
leukocyte adhesion molecule to be induced by IL-1 and TNF (Osborn
et al, 1989). VCAM-1 expression rises by 4 h, and peak expression
occurs by 24 h. The third adhesion molecule is ICAM-1, which is
constitutively expressed on endothelial cells, and its IL-1- or TNF-α-
induced expression rises by 4 h and reaches plateau levels at 24 h
(Pober et al, 1986). During inflammation there is a sequential movement
of cells from blood to tissues, with neutrophils predominating in the
first 24 h and monocytes and lymphocytes predominating thereafter.
This sequence of cell accumulation may be explained by the sequentially
increased expression of E-selectin, VCAM-1, and ICAM-1.
VEGF was recently found to be produced by human KC and is a
powerful mitogen for endothelial cells, implying that it may sustain
angiogenesis during physiologic tissue repair and in pathologic states
accompanied by neovascularization (Ballaun et al, 1995).
KC-DERIVED CHEMOKINES
Chemokines are thought to play a central role in the recruitment and
activation of leukocytes during inflammatory responses. Structurally,
chemokines form a superfamily of proteins that are related by a four-
cysteine motif. The superfamily is subdivided into two branches based
upon whether the first two cysteines in the motif are either adjacent
(termed the C-C chemokines or β-chemokines) or separated by an
intervening residue (the C-X-C chemokines or α-chemokines). KC
are able to produce many C-X-C chemokines, including IL-8, Gro,
epithelial-derived neutrophil attractant-78 (ENA-78), and IP-10, and
a few C-C chemokines, including MCP-1 and RANTES (an acronym
for regulated upon activation, normal T cell expressed, and secreted).
IL-8 is a neutrophil chemotactic factor as well as being chemotactic
for lymphocytes, basophils, and KC, and stimulates basophils to release
histamine.
VOL. 4, NO. 2 SEPTEMBER 1999
C-C chemokines predominantly stimulate monocytes. The human
macrophage chemotactic activation factor (MCAF) and MCP-1 have
been detected from human KC (Barker et al, 1991). MCP-1 and
RANTES are able to induce basophil histamine release, and RANTES
induces the migration and activation of eosinophils. Viewed as a whole,
it is apparent that various components in the skin are affected by KC-
derived cytokines by a complex interplay of different factors in the
microenvironment.
ROLE OF TNF-α IN THE SKIN
Cytokines play a pivotal role in maintaining homeostatic mechanisms
required for the good condition of the host, but any imbalance in the
production and action of cytokines and/or their receptors and cellular
response elements will disturb homeostatic processes, leading to pathol-
ogic consequences. TNF-α is a cytokine with pleiotropic effects upon
cell growth, inflammation, and immune responsiveness. Whereas the
local effects of TNF-α are usually beneficial to the host, when generated
at higher concentrations within chronic inflammatory lesions the
proinflammatory effects of TNF-α often become deleterious and
systemic. Using receptor-lacking mice, we recently found that TNF-
R1(–) mice show hyperresponsiveness to contact allergens but hypores-
ponsiveness to irritants (Kondo et al, 1995), whereas TNF-R2(–) mice
show hyporesponsiveness to contact allergens but normal responses to
irritants (Kondo and Sauder, 1997). TNF-α injection in those mice
revealed that large amounts of TNF-α induce less inflammation in
TNF-R1(–) mice but a normal response in TNF-R2(–) mice, and that
small amounts of TNF-α induce reduced inflammatory reactions in
both receptor-lacking mice. These results suggest that the balance
between the local concentration of TNF-α and the levels of expression
of TNF receptors appears to regulate the effect of TNF-α.
DIFFERENTIAL EFFECTS OF UVA AND UVB ON
CYTOKINE PRODUCTION FROM KC
Many studies have shown that UVB affects human KC to produce a
variety of cytokines that play important roles in various pathophysiologic
conditions observed in the skin exposed to sunlight. The skin is also
exposed to UVA, which has been shown to have an augmentative effect
on UVB-induced erythema formation and carcinogenesis; however,
controversial findings have been reported about the effects of UVA on
KC in terms of the regulation of cytokine expression and production.
As the cytokine microenvironment present during initial activation of
lymphocytes is one of the most important signals to affect Th1 and
Th2 differentiation, which modulates the immunologic function, the
contribution of UVA-induced KC-derived cytokines to the local
cytokine milieu should not be neglected. IL-1α was reported to be
suppressed or not affected by UVA exposure (Chung and Youn, 1995;
Imokawa et al, 1996; Morita et al, 1997). On the other hand, a
significant induction of this cytokine with UVA was observed in other
studies (Corsini et al, 1997; Tebbe et al, 1997). UVA was not found to
induce IL-6 production from KC (Kirnbauer et al, 1991; Morita et al,
1997), whereas a much lower dose of UVA seems to induce IL-6
(Imokawa et al, 1996). Although the reason for these differences in
findings remains unclear, variations of the experimental protocols,
including the light sources, cells, and doses and wavelengths of UVA
may be involved.
Using normal human KC, we examined mRNA expression and
protein production after irradiation with a physiologic dose of UVA,
less than 20 kJ per m2, which is about one-tenth to one-twentieth the
minimal erythematous dose of UVA. In contrast to UVB, UVA did
not induce IL-10, GM-CSF, TNF-α, and TGF-β, whereas IL-1α, IL-
6, IL-8, and IL-12 (p40) were found to be induced by UVA irradiation
(data not shown), suggesting that UVA augments UVB-induced
inflammation via IL-1α but modulates skin immune function distinct-
ively from UVB by inducing different series of immuno-modulatory
cytokines from KC (Kondo and Jimbow, 1998). Considering that IL-
12 is a potent mediator for Th1-type differentiation of T helper cells
and that UVB-induced immune suppression has been shown to be
blocked by IL-12 administration (Schwarz et al, 1996), UVA may play
a counter-regulatory role in UV-induced immunosuppression. Thus,
KERATINOCYTE-DERIVED CYTOKINES 181
Figure 8. Biologic effects depend on the concentrations of cytokines.
Knockout mouse systems demonstrate conditions that may be deleterious for
the body. Highly specific neutralizing antibody studies and additional studies
using recombinant molecules give information about conditions where
various concentrations of cytokines are present. Transgenic mouse systems
exhibit conditions that may include both beneficial and deleterious effects.
under physiologic conditions, solar radiation containing both UVA and
UVB may be not only deleterious but also beneficial for the body.
PITFALLS OF THE RESEARCH ON CYTOKINES
The redundancy of many cytokine functions has been noted; however,
it remains unclear why certain activities of a cytokine should be unique
and others redundant. Compensatory mechanisms may exist for those
cytokine functions whose inappropriate or excessive production would
not be pathogenic or whose constitutive production is beneficial for
an organism. By contrast, cytokine-specific functions might be those
that should be tightly regulated to avoid the pathologic consequences
of their inadvertent expression.
Because cytokines are so potent that very small amounts in local
areas may have a significant effect on other cell types, it is important
to know what kinds of cytokines are present locally. Effects of cytokines
are different depending not only on their concentrations but also on
timing and the sites of the body where they work. Therefore, their
quantity and kinetics are key factors to elucidate to what extent those
cytokines regulate pathophysiologic conditions. In some cases they
have beneficial effects to maintain homeostasis of the body, but in
other cases even with the same amount but with a different timing or
body condition, they may have deleterious effects and contribute to
the induction of pathologic consequences.
There are a number of studies that have tried to find functions and
roles of each cytokine in vitro and in vivo through the use of recombinant
molecules and of highly specific neutralizing antibodies against them;
however, it should be noted that many in vitro studies use unphysiologic
doses of cytokines to see their effects. Further insights into the
physiologic roles of each cytokine have emerged from analyses of
knockout mice in which a cytokine or cytokine receptor gene has
been inactivated, or transgenic mice in which a cytokine gene has
been overexpressed in a target tissue, such as epidermis. These models,
however, also have several disadvantages that should be considered
when the results derived from those mice are extrapolated into human
systems. For example, cytokine-knockout mice exhibit a condition
where no cytokine activity is present in the mice but presumably other
cytokines compensate for the deficient cytokine. Thus, as each approach
has a limitation and covers only some parts of the complex biologic
phenomena mediated by cytokines (Fig 8), multifocal analyses by
incorporating all these studies should be employed to elucidate the
precise role of each cytokine.
This work was supported in part by a Grant-in-Aid for Scientific Research (No.
10670800) from the Ministry of Education, Science and Culture of Japan.
182 KONDO
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