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Nephrology 18 (2013) 243–255

Review Article

The role of cytokines in the pathogenesis of systemic lupus

erythematosus – from bench to bedside
DESMOND YAT HIN YAP1 and KAR NENG LAI1,2
1
Division of Nephrology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, and 2Nephrology Center, Hong Kong Sanatorium and
Hospital, Hong Kong SAR

KEY WORDS: ABSTRACT:

BLys, IFN, IL-6, IL-17, IL-18, TNF, systemic lupus
erythematosus. The pathogenesis of systemic lupus erythematosus (SLE) entails a complex
interaction between the different arms of the immune system. While
Correspondence: autoantibodies production and immune complex deposition are cornered as
Professor Kar Neng Lai, Department of hallmark features of SLE, there is growing evidence to propose the patho-
Medicine, Queen Mary Hospital, The University
genic role of cytokines in this disease. Examples of these cytokines include
of Hong Kong, Hong Kong. Email: knlai@hku.hk
BLys, interleukin-6, interleukin-17, interleukin-18, type I interferons and
Accepted for publication 10 February 2013. tumour necrosis factor alpha. These cytokines all assume pivotal functions
Accepted manuscript online 4 March 2013. to orchestrate the differentiation, maturation and activation of various cell
types, which would mediate local inflammatory process and tissue injury.
doi:10.1111/nep.12047 The knowledge on these cytokines not only fosters our understanding of the
disease, but also provides insights in devising biomarkers and targeted
The authors declared no conflict of interest and
therapies. In this review, we focus on cytokines which have substantial
received no financial support.
pathogenic significance and also highlight the possible clinical applications
of these cytokines.
SUMMARY AT A GLANCE
In this review article, Yap and Lai
summarize the advances in our
understanding of how important cytokines
influence SLE, and indicate future pathways
in which we might intervene in this
important kidney disease.

INTRODUCTION
Systemic lupus erythematosus (SLE) is an autoimmune dis-
order which has multi-organ involvements. The pathogen-
esis of SLE, which involves the various facets of the immune
system, is complex and perplexing. The orthodox under-
standing of this disease encompasses autoantibodies produc-
tion and immune complex deposition, which will give rise
to the subsequent autoimmune phenomenon. However,
mounting evidence has emerged to suggest the crucial role
of various cytokines in the pathogenesis of SLE. These
cytokines are soluble factors which are vibrant mediators for
the differentiation, maturation and activation of the various
immune cells. The consequence of such would be an
immune dysregulation followed by local inflammatory proc-
esses and tissue damage. The understanding of these
cytokines not only enhances our perception of SLE, but also
instills novel ideas for the design of biomarkers and thera-
peutic agents. In this review, we highlight the cytokines
which exert significant effects on the pathogenesis of SLE
and their clinical applications.
INTERLEUKIN 6 (IL-6)
IL-6 is one of the first cytokines studied in the pathogenesis
of SLE due to its close link with B lymphocytes. This cytokine
is primarily secreted by the monocytes, fibroblasts and
endothelial cells although the T- and B- lymphocytes also
contribute to its production. It has an elaborated interaction
with other cytokines as its levels is boosted by IL-1, IL-2 and
tumour necrosis factor-a (TNF-a) but diminished by IL-4,
IL-10 and IL-13. One of the crucial effects of IL-6 is to
promote B lymphocyte maturation into plasma cells and
enhance immunoglobulin production.1,2 Its pleiotropic

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Nephrology © 2013 Asian Pacific Society of Nephrology 243
DYH Yap and KN Lai

actions also include the upregulation of IL-2 and its receptor Role of IL-6 in human SLE
expression, stimulation of platelet production, promotion of
In human lupus patients, the serum IL-6 levels correlated
macrophage and osteoclast differentiation and synthesis of
positively with the disease activity and anti-DNA levels.14,15
acute phase reactants.2 IL-6 receptors (IL-6R) belong to the
Lymphoblastoid cells isolated from lupus subjects expressed
type 1 cytokine receptor superfamily and comprise two
heightened levels of IL-6 while an blockade of IL-6 will result
subunits (IL-6R and the gp130). The coupling of IL-6 and its
in diminution of anti-dsDNA in vitro.16 When compared with
receptor is followed by gp130 dimerization, Jak1 activation
healthy individuals, B lymphocytes recovered from SLE
and GP130 tyrosine phosphorylation.2 Such process is recog-
patients spontaneously generated increased quantity of cir-
nized as the classical IL-6 signalling pathway in which
culating immunoglobulins. IL-6 blockade significantly abro-
membrane-bound IL-6R is required and is largely restricted
gated this spontaneous immunoglobulin secretion, but was
to hepatocytes, some epithelial cells and leucocytes.3
restored with exogenous administration of IL-6.15 It had been
Whereas in the alternative pathway, gp130 protein express-
shown that B lymphocytes from lupus patients had sponta-
ing cells – even in the absence of membrane-bound IL-6R
neous anti-dsDNA production and this autoantibody synthe-
can be stimulated by the complex of IL-6 and the soluble
sis ex vivo was predominantly secreted by low density B
IL-6R and this process is known as trans-signalling.3–5 The
lymphocytes.17 One should appreciate that IL-6 can assist
pathogenic role of IL-6 in SLE had been elucidated in the
these low density B cells from active lupus subjects to differ-
following animal and human studies.
entiate directly into Ig-secreting cells.17,18 CD5 expression
suppressed BCR signalling in SLE B lymphocytes and IL-6
downregulated CD5 expression via DNA methylation and
Role of IL-6 in lupus mice models hence facilitated the activation and expansion of autoreac-
tive B cells in SLE patients.19
In MRL/lpr mice, investigators have observed an age-related
Genetic polymorphisms of the functional interleukin-6
increase of serum IL-6 levels, soluble IL-6 receptors and
(IL-6) promoter appear to confer susceptibility of SLE in
aberrant expression of the IL-6 receptors.6,7 It should be
ethnically different populations. For instance, the IL-6–174
underscored that no other cytokine studies have been dem-
G/C gene polymorphisms would predispose to SLE in Cau-
onstrated to possess the capacity of inducing IgG anti-DNA
casians but such observation is less well established in
antibodies directly. In the NZB/W mice, exogenous adminis-
Asians.20–22 Apart from its systemic effects, IL-6 was shown to
tration of recombinant human IL-6 would lead to an accel-
have a tight link with lupus nephritis. Several studies dem-
erated glomerulonephritis.8 In IL-6-deficient MRL/lpr mice,
onstrated elevated urinary IL-6 excretion in patients with
investigators have observed a substantial diminution of infil-
active proliferative lupus nephritis who also had high titres of
trating macrophages in the kidney, a decrease in renal IgG
anti-dsDNA antibodies.23,24 Moreover, there was enhanced
and C3 deposition, and a shrunken number of CD4+ and
in situ expression of IL-6 along the glomeruli and tubules in
CD8+ lymphocytes.9 The expression VCAM-1 in the kidneys
lupus nephritis kidneys.25 In patients with neuropsychiatric
was also downregulated in MRL-Fas(lpr) IL-6-/- mice com-
manifestation, there was an excessive IL-6 levels in the cer-
pared with IL-6-intact animals.9 These findings proposed that
ebrospinal fluid.26 Furthermore, SLE patients with ongoing
IL-6 may be a key promoter of lupus nephritis and hence
synovitis (19%) and joint deformities (11%) had raised IL-6
may have a potential role for the treatment of human lupus
levels and such increase correlated with other serological
nephritis. In fact, IL-6 blockade in NZB/W mice could
markers of SLE such as ESR (Erythrocyte Sedimentation
hamper proteinuria, lessen the age-related elevation in anti-
Rate) and anti-dsDNA level.27 While IL-6 is consistently
dsDNA levels and also significantly improve the survival of
reported to be upregulated in SLE patients, C-reactive
these animals.10,11 Serum IL-6 levels were raised in
protein (which is ordinarily induced by IL-6) and serum
B6.Sle1.Yaa mice and such elevation was coupled with the
amyloid precursor protein (both being pentraxin group) are
loss of CD19 + B cells and more primitive B-lymphoid pro-
typically not elevated, and the risk of secondary amyloidosis
genitors in bone marrow.12 IL-6 stimulation could trigger
is uncommon among SLE patients. Recent data have also
transcription factors in these uncommitted progenitor cells,
showed that in SLE patients have specific defect in respond-
which would deter lymphopoiesis but promote myelopoiesis
ing to IL-6 in terms of pentraxin production.28
in SLE. The survival of B lymphocytes can also be attenuated
by IL-6 via the recombination-activation gene (Rag) machin-
Clinical applications of IL-6 in SLE
ery, which are vital for the revision of rearranged immu-
noglobulin V (D) J genes. IL-6 favours the expression of Rags IL-6 and its receptors can serve as biomarkers to monitor
and hence facilitates the rescue of autoreactive B cells from disease activity and treatment response. IL-6 release from
apoptosis.13 In MRL/lpr mice, the deficiency in IL-6 led to a peripheral blood mononuclear cell (PBMC) was associated
delayed onset of lupus nephritis.9 All these findings sug- with disease activity and treatment response in lupus nephri-
gested that IL-6 antagonism is potential useful for the treat- tis patients.29 Other studies have also revealed an upregula-
ment of lupus nephritis. tion of IL-6 agonistic receptor gp130 on peripheral

© 2013 The Authors

244 Nephrology © 2013 Asian Pacific Society of Nephrology

lymphocytes in SLE patients and its level correlated with the
disease activity.30 In a phase I trial of tocilizumab (antagonist
to IL-6 receptor) in patients with SLE, up to 50% of patients
had an improvement in the SLEDAI (Systemic Lupus Ery-
thematosus Activity Index) score of ⱖ4 points.31 There was
also 47% drop in the median anti-dsDNA levels and reduc-
tion in circulating plasma cells in patients receiving tocilizu-
mab treatment.31 Other studies have reported the use of
tocilizumab in cases of refractory SLE.32 Although IL-6 block-
ade could hamper proteinuria, lessen the age-related eleva-
tion in anti-dsDNA levels and also significantly improve the
survival in NZB/W mice,10,11 IL-6-directed therapies have not
been tested in human for the treatment of acute or severe
lupus nephritis.
B LYMPHOCYTES STIMULATORS (BLys)
This cytokine belongs to the tumour necrosis factor ligand
family and the understanding of this cytokine assumes
growing importance due to the recent advancement of SLE
treatment related to the manipulation of BLys.33,34 BLys is
cleaved at the cell surface by furin protease, which leads to
the release of a soluble, biologically active molecule.34 This
cytokine is highly expressed on cells of the myeloid lineage
and its secretion is promoted by interferon-g (IFN-g) and
IL-10.35 It binds to strongly B lymphocytes and is a crucial
factor for B lymphocyte proliferation and immunoglobulin
secretion.36 In BLys-deficient mice, there is significant dimi-
nution in mature B lymphocytes, depressed baseline serum
immunoglobuin levels and a compromised immunoglobulin
response to T cell dependent and independent antigens.37
Three types of BLys receptors have been identified, namely,
BAFFR, BCMA and TACI receptors. BLys can engage to these
three receptors on B lymphocytes, whereas a proliferation-
inducing ligand (APRIL) can only attach to TACI and
BCMA.38 Among these three receptors, the BAFFR receptor
assumes the greatest significance as it mediates most of the B
cell effects. A deficiency in BCMA and TACI receptors in
lupus prone mice display no discernible phenotypic or func-
tional abnormalities.37,39 In contrast, A/WySnJ mice (which
bear a mutated baffr gene) exhibit diminished mature B cell
numbers and antibody levels resembling the BLys-deficient
mice.40 BLys-triggered intracellular events are complex and
conducted via the interaction of BLys receptors and several
TNF receptor-associated factors. Docking of BLys with its
receptors activates phospholipase C-g2 and subsequently the
NF-kB pathways,41,42 which is followed by prolonged B lym-
phocytes survival.
Role of BLys in lupus mice models
In BLys transgenic mice (BLys-Tg mice), excessive produc-
tion of BLys not only results in polyclonal hypergam-
maglobulinemia but also raised autoantibodies (including
anti-dsDNA) titre, circulating immune complexes and renal
© 2013 The Authors
Nephrology © 2013 Asian Pacific Society of Nephrology
Cytokines in systemic lupus erythematosus
immunoglobulin deposition.43 These mice develop autoim-
mune disorders resembling SLE and Sjogren syndrome.43 In
SLE-prone mice such as the (NZB/W) F1 mice and MRL-lpr/
lpr mice, heightened BLys levels are detected at the onset of
disease.44 Treatment of NZB/W F1 mice with soluble TACI-Ig
fusion protein prevented the development of proteinuria and
prolonged the survival of the animals.44 These findings
underscored the involvement of BLys and its receptors in the
development of SLE and hence the TACI-Ig was proposed as
a promising treatment for human autoimmune disease. Fur-
thermore, mice treated with exogenous BLys showed
increased numbers of anti-chromatin B cells and augmented
anti-dsDNA production.45 Deletion of either BLys or BR3
critically impaired B cell maturation beyond the transitional
developmental stages.37,40,44,46 T cell-deficient BAFF trans-
genic (Tg) mice developed SLE similar to T cell-sufficient
BAFF Tg mice, and such features were associated with innate
B lymphocyte activation and pro-inflammatory autoantibod-
ies release. These data suggest that a dysregulated innate
activation of B cells alone can drive disease independently of
the T cells.47
Role of BLys in human SLE
In human lupus patients, the circulating BLys level was
raised in human lupus and is correlated with the anti-dsDNA
level.48 In a survey which measured the serum BLys level and
disease activities, healthy subjects universally exhibits a
normal longitudinal serum BLys profile, whereas escalated
BLys level was observed in SLE patients (persistent rise in
25% and intermittent increase in another 25% of patients).
Increased cerebrospinal fluid levels of a proliferation-
inducing ligand (APRIL) are also observed SLE patients with
neuropsychiatric manifestations.
Clinical applications of BLys in SLE
The antagonism of BLys has been one of the important
progresses in the treatment of SLE. Recently, belimumab was
approved by the Food and Drug Administration (FDA) for
the treatment of SLE. The efficacy and safety of belimumab
in active SLE had been evaluated by two large multicentre
randomized control trials. Both studies have demonstrated
that the use of belimumab is associated with significant
improvement in the SLE Responder Index (defined as ⱖ4
points improvement in SLEDAI) at 52 weeks, reduced SLE
activity and severe flares, as well as a comparable tolerability
profile to placebo.33,34 Analysis of the pooled data from these
two large trials showed that belimumab treatment improved
overall SLE disease activity mostly in the musculoskeletal
and mucocutaneous organ domains and less deterioration
occurred in the haematological, immunological and renal
domains.49 In a post-hoc analysis of the BLISS study, the
rates of renal flare, renal remission, renal organ disease
improvement, proteinuria reduction and serologic activity
245
DYH Yap and KN Lai
all favoured belimumab, although the between-group
differences in most renal outcomes were not significant.
Among the 267 patients with renal involvement at baseline,
belimumab resulted in greater renal improvement among
patients receiving mycophenolate mofetil or those with
active serology at baseline when compared with placebo.50
While these results suggested that belimumab might offer
renal benefits in lupus nephritis patients, this analysis was
limited by the small patient numbers and the post-hoc
nature of this pooled analysis. Currently, belimumab is only
approved for treatment for non-renal SLE. Despite the
success of belimumab, the efficacy and safety of antagonism
of the TACI receptor needs further evaluation. In this
context, the phase III study to examine atacicept (a soluble,
fully human, recombinant fusion protein that targets the
TACI receptor) in combination with corticosteroids and
mycophenolate mofetil was prematurely terminated due to
profound drop in serum immunoglobulins and fulminant
sepsis among the study subjects.51
INTERLEUKIN 17 (IL-17)
IL-17 is a type I transmembrane protein isolated initially
from a rodent CD4+ T cell cDNA library.52 This potent pro-
inflammatory cytokine is primarily released by activated T
lymphocytes (‘Th17 cells’ being the most vibrant producer).
As its name implies, these Th17 cells are a subset of CD4+ T
lymphocytes named for its signature cytokine IL-17. The
distinctive features of Th17 lymphocyte include their origi-
nation from naïve T cells and its characteristic cytokine
profile when aptly primed by exclusive transcription factors.
Apart from Th17 lymphocytes, recent data showed that neu-
trophils, gammadelta T cells and mast cells also abundant
express IL-17.53,54 A total of six family members (IL-17 A to
F) and five receptors (IL-17R A to E) were identified in the
IL-17 family.55 IL-17 possesses potent capacity to recruit
monocytes and neutrophils, assist T cell infiltration and
upregulate adhesion molecule expressions.56,57 Several
important cytokines such as IL-6, IL-21 and IL-23 are in
intimate association with IL-17. IL-6, when combined with
transforming growth factor (TGF)b, was capable of inducing
murine naïve T cells to differentiate into Th17 cells.58,59 On
the contrary, mice deficient in IL-6 would experience defec-
tive Th17 differentiation.58 These observations implied that
the presence of an inflammatory signal is required to trans-
form the naïve T cells to become pro-inflammatory. IL-21 is
another factor which exerts a robust influence for Th-17
differentiation. Unlike IL-6, IL-21 is synthesized by the Th17
cells and T-follicular helper cells but not by antigen present-
ing cells and, hence, been proposed to act in an auto-
amplifier fashion for the Th17 response.59 Animal studies
have also demonstrated that Th17 can be generated from
naïve T cells in an IL-23-dependent fashion.60 In addition,
IL-23 elicits IL-17 secretion by memory T cells.61 Taken
together, these findings suggested the IL-23/IL-17 axis may
246
be a novel yet important pathway in the pathogenesis of
autoimmune disorders. Although naïve CD4+ T cells can
differentiate into Th1, Th2 or Th17 effector subsets, the
cytokine milieu characteristic of SLE patients (IL-2 poor but
IL-6 and IL-21 rich) favours Th17 expansion. Th17 cells can
also act as an independent T helper effector cell subset and
perpetuate inflammation via cytokine release. The hallmark
cytokines secreted by the Th17 cells include IL-17A, IL-17F,
IL-21 and IL-22.62 This collection of cytokines can excite B
lymphocytes, and trigger local inflammation and tissue
injury in SLE. The role of IL-17 in SLE pathogenesis has been
explored in both human and animal models of lupus.
Role of IL-17 in lupus mice models
In MRL/lpr mice, there was enhanced IL-17 mediated tissue
insult after ischemic-reperfusion of the gut.63 Diminished
splenic germinal centre formation as well as suppressed anti-
DNA and anti-histone antibodies levels were observed in
IL-17R-deficient BXD2 mice.64 Furthermore, splenocytes
from SNF1 mice produced more IL-17 than non-
autoimmune B6 mice.65 CD3+CD4-CD8- T cells from MRL/lpr
mice secreted abundant IL-17 and the expression of IL-17
and IL-23 receptors in the lymphocytes from these mice
were upregulated as the disease progressed.66 These lym-
phoid cells from MRL/lpr mice, after treatment with IL-23 in
vitro and transferred to non-autoimmune species, can induce
nephritis.66 Mice lacking IL-17 in FcgR2b-deficient lupus
mouse model showed better survival and were largely pro-
tected from development of glomerulonephritis.67 In lupus-
prone C57BL/6-lpr/lpr mice, IL-23R deficiency was
associated with reduced IL-17-producing cells in the lymph
nodes, decreased anti-DNA antibodies and abrogation of
lupus nephritis.68 These findings denote that an aberrantly
active IL-23/IL-17 axis is responsible for the development of
nephritis in lupus-prone mice.
Role of IL-17 in human SLE
Increased circulating IL-17 and IL-23 levels were seen in
patients with SLE and such elevation correlates with disease
activity.69 Recent data have suggested that a substantial
amount of IL-17 in SLE patients is contributed by the TCR-
ab+CD4-CD8- T lymphocytes.70 These TCR-ab+CD4-CD8- T
cells and Th17 cells are also detected in kidney biopsies from
SLE patients with renal involvement, hence provide strong
evidence for the pathogenic role of IL-17 in lupus nephritis.70
In addition, IL-17 assumes a crucial role for the survival and
proliferation of B lymphocytes and antibody secretion in
human SLE.71 Yang et al. demonstrated the presence of Th17
cells in the PBMC and involved organs of SLE patients and
the percentage increased with disease activity.72 Moreover,
the IL-17 from SLE patients can induce adhesion molecule
mRNA expression and the adhesion of T cells to endothelial
cells.72
© 2013 The Authors
Nephrology © 2013 Asian Pacific Society of Nephrology

Clinical applications of IL-17 in SLE
To date, most of the available data of IL-17 and human lupus
are derived from observational or correlation studies. Hence,
there is limited experience in the manipulation of IL-17 for
the treatment of SLE. Therapeutic approaches that limit the
cognate interaction between T cells and B cells, prevent
inappropriate tissue homing and restore TReg function and
the normal cytokine milieu have been explored.73 Biochemi-
cal characterization of SLE T cells has identified distinct early
and late signalling aberrations, and has allowed the unveiling
of novel molecular targets that can be altered with small
molecules, as well as biomarkers that may predict disease
activity and organ damage.
TYPE I INTERFERONS (TYPE I IFN)
Interferons are proteins, which possess capacity to halt viral
replications: the type I IFN being the most essential ones in
human lupus. Viral DNA and RNA are classical triggers of
type I IFN and the signals are conducted via the Toll-like
receptors (TLR) or the retinoic acid-inducible gene I (RIG-I)
like receptors.74 Double-stranded RNA initiates IFN secretion
via TLR3 while single stranded RNA provokes IFN via
TLR7/8 and the cytosine-phosphate-guanine (CpG) rich
DNA via TLR9.75 Type I IFN are synthesized by all leucocytes
with plasmacytoid dendritic cells (PDC) being the most vig-
orous producer in response to TLR7 or TLR9 activation.76
Several mechanisms of how IFN may contribute to the
pathogenesis of SLE have been postulated. Immune com-
plexes generated from autoantibodies and auto-antigens can
activate the dendritic cells, and hence augmented the
antigen presentation and boosted IFN secretion.77 IFN can
amplify the expression of auto-antigen such as Ro52 and also
the release of auto-antigens by translocation of Ro52 to the
nucleus with subsequent induction of apoptosis.78,79 Other
actions include the promotion of dendritic cell maturation
and upregulation of cell surface molecules (MHC classes I
and II, co-stimulatory molecules).80 These concerted effects
coordinate the development of Th1 response. In addition,
type I IFN also promote antibody production and class
switching, reduce B lymphocyte selectivity for CpG-rich
DNA and allow stimulation of B lymphocytes even by non-
CpG DNA.81,82
Role of type I IFN in lupus mice models
When treated with polyinosinic : polycytidylic acid (a syn-
thetic double-stranded RNA ligand for TLR-3 that strongly
induces type I IFN response), autoimmune prone mice
would exhibit enhanced anti-dsDNA antibodies levels,
increased immune complex deposition, accumulation of acti-
vated lymphocytes and macrophages, and augmented met-
alloproteinase activity. These changes were followed by
accelerated lupus nephritis and death of the animals.83–85
© 2013 The Authors
Nephrology © 2013 Asian Pacific Society of Nephrology
Cytokines in systemic lupus erythematosus
Similar findings were observed in murine models injected
with adenovirus expressing IFN-a, which would lead to sus-
tained release of that cytokine, thereby put forward the
pathogenic role of Type I IFN in lupus nephritis.85–89 Addi-
tional evidence indicating the pivotal role of type I IFN in
lupus nephritis derives from studies in New Zealand Black
(NZB), New Zealand mixed 2328 as well as pristane-treated
mice deficient of the receptor of type I IFN (IFNAR-/-). The
defective signalling through IFNAR in IFNAR-/- mice con-
ferred protection from kidney manifestations and was asso-
ciated with a reduction in the titres of lupus-specific
autoantibodies and disease severity. In these lupus mouse
models, the activation and proliferation of dendritic cells as
well as B and T lymphocytes was decreased.90–92
The role of TLR, especially of TLR-7 (responsive to ssRNA)
and TLR-9, (responsive to hypomethylated CpG-rich DNA)
in type I IFN production in lupus is well documented. The
importance of type I IFN and TLR-7 signalling in aggravating
kidney injury was established in mice that overexpress TLR-7
(Y-linked autoimmune accelerating locus mice – Yaa mice) or
that were treated with pristane.93–95 In a pristane-induced
mouse model of SLE, it was shown that an intact type I IFN
signalling pathway is prerequisite to the upregulation of
TLR-7 receptors in B cells and effective activation through
TLR-7 and TLR-9 of B cells to produce lupus-specific auto-
antibodies.96 These findings suggested that type I IFN is
upstream of TLR signalling in the activation of autoreactive B
cells in SLE. Furthermore, in lupus-prone mice, severe
nephritis can be induced by the activation of TLR-9 signalling
pathway through CpG-rich DNA.97 These observations were
supported by a study that tested a dual inhibitor of TLR-7 and
TLR-9 (known to inhibit IFN-a production by PDC) in lupus-
prone mice. The inhibition of TLR-7 and TLR-9 would lead to
a significant improvement of proteinuria, glomerulonephri-
tis, and survival as well as decreased nucleic acid-specific
autoantibodies.98
Role of type I IFN in human SLE
Elevation of type I IFN in lupus patients was one of the first
described cytokine abnormalities in autoimmune diseases.
The link between IFN levels and disease activity, anti-dsDNA
levels and clinical manifestations backs the role of IFN in SLE
pathogenesis.99 In lupus patients, PDC was detected in the
dermal lesions and are responsible for sustained IFN release,
although their circulating number is lower in the peripheral
blood.100 Migration of PDC to the glomeruli is observed in
patients with lupus nephritis and this movement is thought
to be influenced by IL-18.101 In patients with cerebral lupus,
autoantibodies with the capacity to form very potent inter-
feronogenic immune complexes together with RNA-
containing auto-antigens were detected in the cerebrospinal
fluid.102 Gene expression profiling showed that SLE patients
expressed IFN-inducible genes in PBMC and the expression
correlated with disease activities.78 These findings revealed
247
DYH Yap and KN Lai
that raised IFN levels are capable of altering gene expression
in active lupus patients and supported the pathogenic role of
type I IFN in human lupus. Data derived by the genetic
studies had further delineated the causal role of IFN in SLE.
Transcription factor IRF5 was the first identified gene directly
involved in IFN production and was associated with height-
ened risk of SLE.103 Lupus patients with a risk haplotype of
IRF5 showed more intense serum IFN activity when com-
pared with patients lacking this risk genotype and the effect
was most obvious in patients with autoantibodies against
either RNA-binding proteins or double-stranded DNA.104
Another example is the signal transducer and activator of
transcription 4 (STAT4) which interacts with the cytoplasmic
part of the IFNAR and variants of STAT4 have been shown to
be strongly associated with lupus.105 A link between the IFN
response and SLE had also been established for patients with
polymorphism of Jak TYK2.106 Healthy first degree relatives
of lupus patients have more pronounced serum IFN activity
and the levels are more abundant in younger individu-
als.107,108 A combination of risk alleles in the type I signalling
pathway (e.g. STAT4 and IRF5) may confer an additive pre-
disposition of disease.109 It can be inferred that the use of
genetic mapping may help predicting the development and
severity of disease in the future.
Clinical applications of type I IFN in SLE
Interferon-regulated chemokines may be employed to
monitor disease activity and organ damage.110,111 It has also
been proposed that type I IFN-inducible mRNA can be
used as pharmacodynamic markers to monitor treatment
response of anti-IFN therapy in SLE.112 The use of anti-IFN-a
in the treatment of moderately active SLE was examined in
a phase I multicentre double-blind randomized trial. In that
study, the use of sifalimumab (an anti-IFN-a monoclonal
antibody) led to a dose-dependent inhibition of type I IFN-
induced mRNA in whole blood and corresponding changes
in related proteins in affected skin. Exploratory analyses
showed consistent trends towards improvement in disease
activity, less requirement of new or escalation of immuno-
suppressive treatments and fewer flares in sifalimumab-
treated patients.113 Tolerability profile was acceptable and
comparable to patients receiving placebo.
TUMOUR NECROSIS FACTOR-a (TNF-a)
Tumour necrosis factor-a is expressed as a trimer on cell
surface and in soluble form after the activation of macro-
phages and dendritic cells. Being described to have both
protective and deleterious effects in SLE, its position in lupus
pathogenesis remained controversial.
Role of TNF-a in lupus mice models
In NZB/W mice, there was diminished production of TNF-
a.114 In some mouse model, the deficiency of TNF-a
248
appeared to provoke lupus-like autoimmunity. While TNF-a
defective NZB/W mice develop severe disease manifesta-
tions, TNF-a intact NZB/W mice only show modest lupus
activity.115 Conversely, TNF-a concentration was elevated in
both sera and renal tissue of MRL/lpr lupus mice and the
levels of TNF-a correlated with the severity of kidney dis-
ease.116 Moreover, even in NZB/W mice, renal expression of
TNF-a is escalated in conjunction with kidney inflamma-
tion.117 In MRL/lpr mice, anti-TNF-a therapy led to improve-
ment of joint and lung manifestations.118,119 Whether the
controversial role of TNF-a in the pathogenesis of murine
SLE could be related to the different animal models used
remains unclear.
Role of TNF-a in human SLE
The circulating TNF-a level in active SLE patients closely
followed the disease activity and elaborated TNF-a expres-
sion was seen in the renal parenchymal tissue in patients
with lupus nephritis.29,120 Nonetheless, conflicting evidence
exists in subjects who had received anti-TNF-a therapy for
other autoimmune disorders.121,122 These individuals devel-
oped lupus-like features coupled with elevated anti-nuclear
factors, anti-dsDNA and anti-cardiolipin antibodies. Resolu-
tion of these symptoms and autoantibodies followed the
cessation of TNF-a blocking therapy. Recent studies on
inflammatory bowel disease and ankylosing spondylitis also
showed that TNF-a blockade might cause drug-induced
lupus.123–128 However, anti-TNF-induced SLE is a rela-
tively uncommon phenomenon and these patients often
only develop multiple autoantibodies but mild clinical
manifestations.
Clinical applications of TNF-a in SLE
Given the findings of elevated serum TNF-a in active SLE
and overexpression of TNF-a in active lupus nephritis,29,129
TNF-a antagonism still appears to be an attractive option for
the treatment of active lupus disease. However, evidence for
therapeutic efficacy of TNF-a blockade in SLE is still lim-
ited.130,131 A recent study which reviewed the experience of
using inflixmab in SLE patients had raised serious concern of
fulminant sepsis and malignancy, and hence the decision to
use anti-TNF-a blockade in SLE should not be taken
lightly.132
INTERLEUKIN-18 (IL-18)
IL-18 belongs to the IL-1 family and is synthesized in an
inactive form which requires cleavage by caspase-1 to
become biologically active. It exerts a variety of effects on
dendritic cells, T lymphocytes and natural killer cells, and is
a potent inducer of IFN-a to promote Th1 differentiation.
The following discussion focused on the role of IL-18 in the
pathogenesis of SLE.
© 2013 The Authors
Nephrology © 2013 Asian Pacific Society of Nephrology

Fig. 1 Schematic diagram to illustrate the complex interaction of different cytokines/immune cells and the rationale of anti-cytokine therapies. IL, interleukin;
TNF-a, tumour necrosis factor-a.
Role of IL-18 in murine SLE
When compared with wild-type MRL/++ mice, MRL/lpr
mice demonstrated higher circulating IL-18 levels and daily
injections of IL-18 or IL-18 plus IL-12 resulted in accelerated
proteinuria, glomerulonephritis, vasculitis and elevated
levels of pro-inflammatory cytokines in these animals.133
Moreover, increased IL-18 expression was observed in the
lymph nodes and kidneys of MRL/lpr mice.134 In MRL/lpr
mice, there were renal upregulation of mature IL-18, which
was primarily detected in the tubular epithelial cells and such
increased expression was in parallel with the severity of
nephritis.135 Recent studies have also further characterized
the role of IL-18 in SLE using signal transducers and activa-
tors of transcription 4 (Stat4) knockout MRL/lpr mice and
found that they did not differ in survival or renal function
from Stat4-intact MRL/lpr mice. The circulating IL-18 levels,
however, were elevated in Stat4-deficient mice compared
with Stat4-intact ones, suggesting the contributory role of
IL-18 in the progression of lupus nephritis independent of
Stat4.136 When vaccinated with autologous IL-18, MRL/lpr
© 2013 The Authors
Nephrology © 2013 Asian Pacific Society of Nephrology
Cytokines in systemic lupus erythematosus
mice would develop anti-IL18 autoantibodies and these mice
displayed a substantial decrease in IFN-a synthesis, alleviated
glomerulonephritis and renal damage, and improved sur-
vival,137 indicating an important pathogenic role of this
cytokine.
Role of IL-18 in human SLE
Increased serum IL-18 levels had been observed in SLE
patients and an association with renal manifestations has
been reported.138–140 Serum IL-18 was higher in lupus
patients than in controls and its level was correlated with
urinary microalbumin.141 Moreover, IL-18 expression was
also increased within the glomeruli of lupus nephritis
patients and such expression was primarily detected within
the mesangial matrix and in infiltrating mononuclear cells.141
Moreover, several studies have described higher circulating
IL-18 in SLE patients than in control subjects, and the levels
correlates with the anti-dsDNA titres and the SLEDAI
score.138,140,142,143 Apart from the kidneys, IL-18 was also
249
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Table 1 Cytokines which have important pathogenic roles in SLE: the major secreting cells and current clinical applications.

Cytokines Major secreting cells Current clinical applications

IL-6 Monocytes 1. Phase I trial of tocilizumab showed improvement in the SLEDAI score of ⱖ4 points, reduction in anti-dsDNA
Fibroblasts and circulating plasma cells.31
Endothelial cells 2. Tocilizumab has been used in cases of refractory SLE.32
BLys Monocytes 1. Use of belimumab is associated with significant improvement in the SLE Responder Index (defined as ⱖ4
Macrophages points improvement in SLEDAI) at 52 weeks, reduced SLE activity and severe flares, as well as a
Dendritic cells comparable tolerability profile when compared with placebo.33,34
Activated neutrophils 2. Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and
mucocutaneous organ domains while less deterioration occurred in the haematological, immunological
and renal domains.49
IL-17 Th-17 Lymphocytes Still under investigation
Type 1 interferon Plasmacytoid 1. Use of sifalimumab (anti-IFN-a monoclonal antibody) led to a dose-dependent inhibition of type I
(IFN) dendritic cells IFN-induced mRNA in whole blood and corresponding changes in related proteins in affected skin.113
2. Exploratory analyses showed consistent trends towards improvement in disease activity, less requirement
of new or escalation of immunosuppressive treatments and fewer flares in sifalimumab-treated patients.113
TNF-a Macrophages 1. Infliximab (anti-TNF-a) improved joint symptoms and proteinuria in SLE patients with moderate activity.130
Dendritic cells 2. Infliximab (anti-TNF-a) resulted in sustained remission in class IV lupus nephritis patients who failed to
achieve remission with steroid/MMF/cyclosporine.147

BLys, B lymphocytes stimulator; IL, interleukin; MMF, mycophenolate mofetil; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Activity
Index; TNF-a, tumour necrosis factor-a.

highly relevant in other organ manifestations of lupus. IL-18
was abundantly expressed in biopsy samples of lesional skin
from patients with cutaneous lupus.144 These patients also
expressed higher levels of IL-18 receptor on their keratino-
cyte surface in response to TNF-a and IFN-g stimulation.
Kahlenberg et al. have recently demonstrated that inflamma-
some activation of IL-18 would result in endothelial progeni-
tor cell (EPC) dysfunction in SLE patients, which might
explain premature atherosclerosis in SLE. In these experi-
ments, neutralization of IL-18 in SLE EPC cultures restores
their capacity to differentiate into mature endothelial cells,
supporting a deleterious effect of IL-18 on vascular repair
in vivo.145
Clinical applications of IL-18 in SLE
Nold et al. demonstrated that the use of a IL-18 binding
protein would significantly inhibit the release of IFN-a and
matrix metalloproteinase-9 (MMP-9) from whole blood
samples obtained from SLE patients, and anti-IL18 might
confer additional inhibitory effect on the pro-inflammatory
cytokines when compared with samples incubated with cor-
ticosteroids or mycophenolic acid alone.146 Although IL-18
blockade appeared to a potential therapeutic concept in SLE,
the clinical data regarding this approach are still lacking.
CONCLUDING REMARKS
In this review, we have highlighted the cytokines which have
crucial pathogenic significance in SLE (Fig. 1). The growing
knowledge in these cytokines has introduced opportunities
for the design of innovative diagnostics and therapeutic
approaches (Table 1). Currently, these novel therapies which
involve the attenuation of the cytokine system are often used
as add-on treatment or for recalcitrant cases. However, one
should expand the use of these biologics such as minimiza-
tion of other immunosuppressive drugs which have more
significant toxicities. While some of these agents have
proven efficacy and tolerability in the initial studies, the
long-term safety remains undefined. Both upcoming rand-
omized trials and long-term follow-up studies are needed to
adequately address these concerns. Taken together, data
regarding the manipulation of the cytokine systems are
encouraging and it is worthwhile to invest resources for the
development of therapy in this promising direction.
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