Cytokine 73 (2015) 326334

Contents lists available at ScienceDirect

Cytokine
journal homepage: www.journals.elsevier.com/cytokine

The role of cytokines in the pathogenesis of cutaneous lupus

erythematosus
E.S. Robinson, V.P. Werth
Veteran Affairs Medical Center, Philadelphia, PA, United States
Department of Dermatology, University of Pennsylvania, Philadelphia, PA, United States

a r t i c l e

i n f o

Article history:
Received 11 September 2014
Received in revised form 24 January 2015
Accepted 28 January 2015
Available online 9 March 2015
Keywords:
Cutaneous lupus erythematous
Ultraviolet light
Interferon
Interleukin
Tumor necrosis factor-alpha

a b s t r a c t
Cutaneous lupus erythematosus (CLE) is an inammatory disease with a broad range of cutaneous
manifestations that may be accompanied by systemic symptoms. The pathogenesis of CLE is complex,
multifactorial and incompletely dened. Below we review the current understanding of the cytokines
involved in these processes. Ultraviolet (UV) light plays a central role in the pathogenesis of CLE, triggering keratinocyte apoptosis, transport of nucleoprotein autoantigens to the keratinocyte cell surface and
the release of inammatory cytokines (including interferons (IFNs), tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, IL-8, IL-10 and IL-17). Increased IFN, particularly type I IFN, is central to the development of CLE lesions. In CLE, type I IFN is produced in response to nuclear antigens, immune complexes
and UV light. Type I IFN increases leukocyte recruitment to the skin via inammatory cytokines, chemokines, and adhesion molecules, thereby inducing a cycle of cutaneous inammation. Increased TNFa in CLE
may also cause inammation. However, decreasing TNFa with an anti-TNFa agent can induce CLE-like
lesions. TNFa regulates B cells, increases the production of inammatory molecules and inhibits the production of IFN-a. An increase in the inammatory cytokines IL-1, IL-6, IL-10, IL-17 and IL-18 and a
decrease in the anti-inammatory cytokine IL-12 also act to amplify inammation in CLE. Specic gene
mutations may increase the levels of these inammatory cytokines in some CLE patients. New drugs targeting various aspects of these cytokine pathways are being developed to treat CLE and systemic lupus
erythematosus (SLE).
Published by Elsevier Ltd.

1. Introduction to cutaneous lupus erythematosus

Lupus erythematosus (LE) encompasses a broad range of cutaneous symptoms including malar rash, discoid rash, photosensitivity and oral ulcers as well as systemic symptoms such as
arthritis, renal disease, abnormal serologies and hematologic disease. Patients may have cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE) or both. The American College of
Rheumatology denes SLE as the presence of at least four of eleven
diagnostic criteria. The prevalence of SLE varies worldwide from 17
to 48 per 100,000 people. The prevalence of CLE is approximately
equal to that of SLE [1].
CLE is a heterogeneous disease that includes a wide variety of
cutaneous symptoms. Gilliam and Sontheimers classication of
CLE identies three types of histopathologic LE-specic lesions:

Corresponding author at: Department of Dermatology, Perelman Center for

Advanced Medicine, Suite 1-330A, 3400 Civic Center Boulevard, Philadelphia, PA
19104, United States. Tel.: +1 215 823 4208; fax: +1 866 755 0625.
E-mail address: werth@mail.med.upenn.edu (V.P. Werth).
http://dx.doi.org/10.1016/j.cyto.2015.01.031
1043-4666/Published by Elsevier Ltd.

acute CLE (ACLE), subacute CLE (SCLE) and chronic CLE (CCLE)
[2]. ACLE most commonly presents with erythematous macules
and papules classically in a malar (buttery) distribution along
with positive antinuclear, anti-double stranded deoxyribonucleic
acid (dsDNA) and anti-Smith (Sm) antibodies. ACLE is often associated with systemic symptoms. SCLE presents with annular or
papulosquamous morphologies. Patients with SCLE are highly photosensitive. Seventy percent of SCLE patients have anti-Ro/SSA
antibodies, 7080% have antinuclear antibodies and 5% have antidsDNA antibodies [3,4]. Fifty percent of SCLE patients meet criteria
for SLE, although they often have mild SLE symptoms [5]. CCLE
includes tumid lupus, lupus panniculitis, chilblain lupus and discoid lupus erythematosus (DLE). CCLE patients, less frequently
those with localized discoid lupus and tumid lupus, develop SLE,
but when they meet SLE criteria it is frequently with non-organthreatening criteria [6]. However, patients with SLE can develop
CCLE-type lesions. Patients with CCLE rarely have positive
antinuclear, anti-dsDNA or anti-Sm antibodies. They may have
low-titer anti-Ro/SSA antibodies [7]. In addition to the LE-specic
lesions of ACLE, SCLE and CCLE described above, Gilliam and

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Sontheimer identied non-specic LE lesions. These non-specic

LE lesions include Raynauds phenomenon, vasculopathy, leukocytoclastic vasculitis, livedo reticularis and alopecia.
CLE can cause signicant disability and decreased quality of life.
CLE patients have equivalent or worse mental health than patients
with recent myocardial infarctions, congestive heart failure, type 2
diabetes or chronic hypertension [8]. Quality of life in CLE is particularly impaired for women and patients with a generalized distribution of CLE lesions or severe disease. Improvement of CLE skin
disease activity as measured by the CLE Disease Area and Severity
Index (CLASI) correlates with an improvement in skin-specic
quality of life [9].

63% of SCLE, 60% of SLE and 45% of DLE subjects developed skin
lesions after exposure to UV irradiation [12]. Forty-two percent
of lesions were induced by UVB alone and 34% by UVA alone. In
the patients irradiated with combined UVA and UVB, 53% developed skin lesions.
UV light produces CLE lesions through multiple pathways. UV
light induces cytokine and chemokine production, keratinocyte
apoptosis and necrosis, expression of autoantigens on keratinocytes, recruitment of activated immune cells and increased
antibody binding to keratinocytes (Table 1). Through these actions
UV light causes CLE lesions and can aggravate systemic symptoms
in SLE.

2. The pathogenesis of CLE

3.2. UV light-induced production of cytokines and chemokines

The pathogenesis of CLE is multifactorial and incompletely

understood. It involves ultraviolet (UV) light, keratinocyte apoptosis, cytokine release, B cell hyperactivity, and activation of T cells
and dendritic cells. Cytokines play an important role in the pathogenesis of CLE. Cytokines induce and inhibit immune cells and each
other. Their roles may be different in the various CLE subtypes.
Cytokines are grouped into two functional classes: T-helper 1
(Th1) cell-produced cytokines and T-helper 2 (Th2) cell-produced
cytokines. The Th1 group includes interleukin (IL)-2, IL-12, tumor
necrosis factor (TNF)-a and interferon (IFN)-c. These cytokines stimulate cell-mediated immunity. The Th2 group consists of IL-4, IL5, IL-6 and IL-10. These cytokines increase humoral immunity.
Abnormal expression of both Th1 and Th2 cytokines are important in the pathogenesis of tissue injury in lupus. In one study, the
peripheral blood mononuclear cells (PBMC) of CLE patients had
increased expression of the CC chemokine receptor (CCR) 5 (characteristic of Th1 cells) and decreased expression of CCR3 (characteristic of Th2 cells) when compared to healthy controls [10].
Chemokines are proteins involved in the recruitment of inammatory cells and play an important role in executing the cytokine
pathways. The increased ratio of CCR5 to CCR3 in this study suggests a predominantly Th1 immune response in CLE. However, in
another study, UVB irradiation induced a predominantly Th2 cytokine response [11]. It is now thought that both Th1 and Th2 cytokines play important roles in CLE. Below we review the current
understanding of the role of cytokines in the development of CLE,
particularly IFNs, TNFa, and ILs. However, rst, we review the role
of UV in the production of these cytokines and the pathogenesis of
CLE.

UV light directly induces cytokine synthesis and release. UV

light triggers keratinocyte and immune cell production of IFN,
TNFa, transforming growth factor (TGF)-b, IL-1a/b, IL-6, IL-8, IL10 and IL-17 [1315]. These cytokines, particularly IL-1a and
TNFa, then trigger the release of additional inammatory epidermal cytokines, inammatory chemokines and adhesion molecules.
These factors recruit inammatory cells into the skin and cause tissue inammation. The pathways of these cytokines are described
in detail shortly.
Chemokine (CXC motif) ligand (CXCL) 9, CXCL10 and CXCL11
are the most highly expressed chemokines in CLE [16]. More
recently, the nding of chemokine (CC motif) ligand (CCL) 27
leakage from the basal epidermis into the papillary dermis in
the skin of LE subjects after UV irradiation points to a new chemokine involved in the development of CLE lesions [16]. CCL27 is a
chemokine that recruits memory T cells into the skin.

3. Ultraviolet light-induced cytokine production and

keratinocyte apoptosis
3.1. Key points
 UV light directly increases the levels of TNFa and certain types
of interferon and interleukin. These cytokines are important in
the pathogenesis of CLE. They mediate the immune cell dysfunction, tissue inammation and tissue injury present in CLE.
 UV light induces keratinocyte apoptosis, which may increase
the release of cytokines and autoantigens.
 Keratinocyte necrosis and the action of UV light on keratinocytes displace nucleoproteins from inside the cell to the
cell surface. Antibodies bind to these nucleoproteins causing
further inammation and tissue injury.
UV light plays a signicant role in the production of cytokines in
CLE and causes typical CLE lesions and photosensitivity. UV light,
particularly UVB (290320 nm), can induce new CLE lesions and
exacerbate existing CLE disease. Seventy-six percent of tumid LE,

3.3. UV light-induced keratinocyte apoptosis and necrosis

In addition to triggering cytokine release, UV light also induces
keratinocyte apoptosis. The keratinocytes of CLE patients are prone
to apoptosis after UV irradiation. In one study DLE lesions had
increased apoptotic keratinocytes in the basal zone and SCLE
lesions had increased apoptotic keratinocytes in the suprabasal
zone compared to controls [17]. Another study found that CLE
lesions had increased p53 expression, a tumor suppressor that is
associated with apoptosis and is upregulated by UV light, TNFa
and IFN-c [18]. DLE lesions, but not healthy control skin, also
had increased expression of Fas and the Fas ligand [19]. The Fas
ligand binds to Fas, a cell surface receptor, to trigger apoptosis.

Table 1
The role of UV light in the pathogenesis of CLE. CCL27 = Chemokine (CC motif) ligand
27. CLE = Cutaneous lupus erythematosus. IFN = Interferon. IL = Interleukin.
TNFa = Tumor necrosis factor-a. UV = Ultraviolet.
Potential
CLE
pathogenic
factors

Primary
source(s)

Primary function

UV light

Sun
Articial
lights

Proinammatory

Primary role(s) in the

pathogenesis of CLE

 Increases production of
inammatory
cytokines
and chemokines such as
IFN, TNFa, IL and CCL27,
which recruit activated
immune cells and cause
tissue inammation
 Triggers
keratinocyte
apoptosis and necrosis
 Increases expression of
autoantigens
on
keratinocytes and antibody
binding to keratinocytes

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These studies describe multiple mechanisms for increased keratinocyte apoptosis in CLE.
There may also be impaired clearance of these apoptotic cells in
CLE. In one study, a high number of apoptotic keratinocytes were
still present in CLE lesions 72 h after UV-irradiation, while in
healthy control skin the apoptotic cells which were visible at
24 h had signicantly decreased by 72 h [20]. This accumulation
of apoptotic keratinocytes can result in secondary necrosis, and
the release of proinammatory cytokines and potential autoantigens [21]. However, other studies found that the number of apoptotic cells, clearance rate of apoptotic cells and level of secondary
necrosis after UV irradiation were not signicantly different in
the skin of SLE patients compared to controls [22,23].
3.4. UV light-induced autoantigens
Keratinocyte apoptosis and necrosis as well as UV irradiation
alone increase the presence of autoantigens in the skin. Both UV
irradiation and keratinocyte apoptosis increase the translocation
of nucleoproteins via blebs to the keratinocyte surface. These
nucleoproteins include CLE-associated autoantigens such as Ro/
SSA (Ro52 and Ro60) [24]. High-mobility group protein B1
(HMGB1), a proinammatory and immunogenic cytokine, is also
released from apoptotic or necrotic keratinocytes and acts as an
autoantigen [25,26]. These autoantigens are then targeted by
autoantibodies, resulting in the release of additional cytokines
and skin inammation [27]. Minimizing sun exposure and
maximizing sun protection are critical in the treatment of LE to
block the multiple UV-induced inammatory pathways.
4. Interferon
4.1. Key points
 Increased IFN, especially type I IFN, plays an important role in
the pathogenesis of CLE.
 In CLE, plasmacytoid dendritic cells (pDCs) produce type I IFN in
response to nuclear antigens, immune complexes and UV light.
Type I IFN increases leukocyte recruitment to the skin via
inammatory cytokines, chemokines and adhesion molecules.
Type I IFN also upregulates the production of cytotoxic proteins.
In total, these actions induce and propagate cutaneous
inammation.
 Mutations in the IFN regulatory factor 5 (IRF5), tyrosine kinase 2
(TYK2) and three prime repair exonuclease 1 (TREX1) genes
increase type I IFN production in some people with CLE.
 Like type I IFN, type II IFN increases the production of chemokines and adhesion molecules that recruit inammatory cells into
the skin. Type II IFN also increases the production of TNFa.
Increased levels of type II IFN are found in SLE. Type II IFNs role
in CLE is unclear.
 Increased type III IFN in the lesions and serum of CLE subjects
points to a potential role for this cytokine in the pathogenesis
of CLE. Like the other types of IFN, type III IFN increases the production of inammatory cytokines.
 Many new drugs are being developed to treat CLE and SLE that
target various aspects of the IFN pathway.
IFNs are important modulators of the immune system.
Increased IFN production was rst identied as a central factor in
the pathogenesis of lupus in 1979 [28]. IFN-a and IFN-b are classied as type I IFNs, while IFN-c is a type II IFN. Type I IFN is involved
in the early activation of innate and adaptive immunity as well as
autoimmunity. It has wide-ranging effects including: stimulating
proliferation and differentiation of B cells into plasma cells, and

monocytes into antigen presenting cells; activating the Th1 pathway; stimulating dendritic cells; suppressing regulatory T cells;
and modifying cytokine effects. Type II IFN inhibits viral replication
to ght infections, activates macrophages, monocytes and tumor
surveillance, and both stimulates and modulates inammation.
Increased IFN, particularly type I IFN, plays an important role in
the development of cutaneous inammation in CLE (Table 2).
4.2. Type I interferon
Type I IFN is elevated in the serum and lesional skin of lupus
patients. In CLE, pDCs residing in the dermis are the primary type
I IFN producing cells. PDCs produce type I IFN in response to nuclear antigens released through apoptosis or necrosis and to autoantibodies in immune complexes (such as anti-dsDNA and anti-U1ribonucleoprotein [RNP] antibodies) via the toll-like receptor
(TLR) 7 or TLR9 as well as through TLR-independent mechanisms
[29]. TLR7 and TLR9 are expressed on pDCs. Other stimulating factors for type I IFN remain poorly dened, but include UV light,
medications, trauma and infection.
IFN-a is composed of 13 subtypes with pleiotropic functions.
IFN-a binds the type I IFN receptor (IFNAR) to activate Janus-activated kinases (JAKs) including TYK2 and JAK1. JAK phosphorylates
signal transducers and activators of transcription (STAT) 1 and
STAT2, which form a complex with other factors. This complex
translocates into the nucleus to initiate gene transcription of IFNstimulated genes. These genes increase IFN signaling, rapidly stimulate further cytokine release and increase leukocyte recruitment into the skin (including memory T cells, cytotoxic T cells
and pDCs) via the proinammatory chemokines CXCL9, CXCL10
and CXCL11 [16].
In particular, CXCL9 on dendritic cells and endothelial cells of the
supercial dermal plexus as well as CXCL10 in the basal epidermis
and perivascular leukocytes recruit chemokine (CXC motif) receptor

Table 2
The role of interferon (IFN) in the pathogenesis of CLE. CD95 = Cluster of differentiation 95. CLE = Cutaneous lupus erythematosus. CXCL = Chemokine (CXC motif)
ligand. IFN = Interferon. JAK = Janus-activated kinase. NK = Natural killer.
pDC = Plasmacytoid dendritic cell. STAT = Signal transducers and activators of transcription. Th1 = T-helper 1. TNFa = Tumor necrosis factor-a. TRAIL = TNF-related
apoptosis-inducing ligand.
Potential
CLE
pathogenic
factors

Primary
source(s)

Primary function

Type I IFN

pDCs

Proinammatory

Type II IFN

Th1 cells NK
cells

Proinammatory

Type III IFN

Keratinocytes

Proinammatory

Primary role(s) in the

pathogenesis of CLE

 Activates transcription
of type I IFN-stimulated genes via the JAK/
STAT pathway, which
recruit leukocytes to
the skin via inammatory
cytokines,
chemokines
(particularly CXCL9 and
CXCL10) and adhesion
molecules
 Increases the level of
cytotoxic
proteins
(perforin and granzyme B) and mediators
of
apoptosis
(CD95 and TRAIL)
 Enhances production
of TNFa, inammatory
chemokines and adhesion molecules
 Increases the level of
the inammatory chemokine CXCL9

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(CXCR) 3-positive effector cells [16]. PDCs also express CXCR3,

allowing pDC-produced IFN to recruit new pDCs into the skin and
further increase the production of IFN from pDCs. Additionally, type
I IFN upregulates cytotoxic proteins, such as perforin and granzyme
B via IFN-c in T cells, the apoptosis receptor cluster of differentiation
95 (CD95) and TNF-related apoptosis-inducing ligand (TRAIL) [30
32]. TRAIL is a keratinocyte-produced IFN-dependent chemokine
(Fig. 1). TRAIL is upregulated in the blood of CLE patients [32].
TRAILs proapoptotic receptor is found on keratinocytes in CLE
lesions and TRAILs production is increased when keratinocytes are
treated with IFN-a [32]. The ultimate result of these processes is
the induction and perpetuation of CLE inammation and disease.
Type I IFNs are also associated with SLE systemic symptoms such
as fever, fatigue, myalgias and arthralgias.
The presence of increased type I IFN in CLE has been reported in
many studies. The type I IFN signature is upregulated in the PBMC
of patients with SCLE and DLE compared to controls, but not subjects with tumid lupus [33]. An increased type I IFN score in CLE
correlated with an increased CLASI activity score, a measure of
CLE disease activity [33]. The presence of IFN-a-inducible genes
such as IRF7 and myxovirus resistance protein A (MxA) in cutaneous LE lesions suggests the presence of IFN-a in CLE [16,34].
PDCs producing IFN-a have been found to inltrate cutaneous LE
lesions, but not normal skin, with the number of pDCs correlating
with MxA, implicating them in local type I IFN production [35]. The
localization of MxA in CLE lesions is the same as the areas of
CXCR3 + T cell accumulation [36]. Wenzel et al. found that the distribution pattern of MxA, CXCL9 and CXCL10 corresponded to the
histological distribution of lymphocytes in different types of CLE
[34]. In DLE and SCLE MxA and CXCL9 were observed in the epidermis and papillary dermis, consistent with interface dermatitis,
while in lupus panniculitis CXCL9 and CXCL10 were predominately
present in the fat in a lobular distribution.
Some genetic mutations that increase type I IFN are implicated
in the pathogenesis of CLE. A genetic polymorphism in IRF5, an
IFN-a-inducible gene that increases type I IFN production, was present in six SCLE, eight DLE and eight SLE subjects out of a total of
219 subjects studied [37]. A polymorphism in TYK2, a JAK that
binds to the IFNAR, is also associated with DLE [37]. Case reports
of a genetic mutation in TREX1, a DNA exonuclease, in SLE and a
familial form of chilblain lupus point to another genetic cause of
LE [38]. Abnormal DNA repair in TREX1-decient cells may result
in DNA accumulation, thereby stimulating IFN-a and, through this
pathway, triggering LE.
Although rare, patients with diseases such as chronic hepatitis,
leukemias, lymphomas and other cancers requiring treatment with
IFN-a can develop SLE- or CLE-like symptoms. These LE-like symptoms include abnormal lupus serologies, a malar rash, a discoid
rash, photosensitivity and renal disease. CLE-like lesions may also
develop at the IFN injection site [39].

4.3. Type II interferon

The role of type II IFN (IFN-c) in the pathogenesis of CLE is still
being determined. Like IFN-a, IFN-c is increased in the serum of
SLE patients, but not all studies found that the serum level of
IFN-c correlated with SLE disease activity [40]. Th1 cells and natural killer (NK) cells stimulated by specic antigens secrete type
II IFN. Type II IFN induces the production of the chemokines
CXCL9, CXCL10 and CXCL11 [16]. Additionally, IFN-c stimulates
the production of intracellular adhesion molecule 1 (ICAM-1) in
human keratinocytes and increases T lymphoblast-keratinocyte
adhesion [41]. IFN-c also induces TNFa production in a dose-dependent manner in unirradiated human keratinocytes [42].
Combining IL-1a with IFN-c synergistically increases TNFa production from these cells. Neither IFN-a nor IFN-b upregulates
TNFa expression in unirradiated human keratinocytes. Because
type II IFN is increased in SLE patients, and it increases the production of chemokines, adhesion molecules and TNFa, it likely plays a
role in the inammation of SLE and possibly CLE.
4.4. Type III interferon
Recent evidence points to type III IFN, IFN-k, as a pathogenic
factor in CLE [43]. Keratinocytes produce high levels of IFN-k in
response to nucleic acids, but not type I or type II IFNs. In turn,
IFN-k produces the chemokine CXCL9. Like type I IFN, type III IFN
functions through the JAK/STAT pathway to induce inammatory
pathways, but it does not target the IFNAR. Instead, type III IFN
binds to a receptor found on epithelial cells [44]. In one study, high
levels of IFN-k and the IFN-k receptor were found using immunohistochemistry in the epidermis of CLE lesions of eight SCLE and
eight DLE subjects compared to weak expression of both in six
healthy controls [43]. Additionally, 28 CLE subjects with active
lesions had increased serum levels of IFN-k. These results point
to a potential role for type III IFN in the pathogenesis of CLE.
4.5. Treatments targeting the interferon pathways
Many available drugs as well as drugs currently undergoing
clinical trials for LE target the IFN pathway. Antimalarial drugs
used for the treatment of CLE, including hydroxychloroquine and
chloroquine, are thought to reduce pDC production of IFN by preventing nucleic acids from acting on TLRs [45]. Early trials for the
treatment of SLE are underway for anti-IFN-a antibodies including
sifalimumab (MEDI-545) and rontalizumab (RG7415). In phase I
and II studies sifalimumab, a human anti-IFN-a monoclonal antibody, decreased expression of type I IFN-induced messenger
ribonucleic acid (mRNA) in whole blood and type I IFN proteins
in skin in a dose-dependent manner as well as improved the clinical disease activity of treated subjects in the phase I study only

TRAIL

Smulated
pDC

TRAIL R1 receptor

IFN-
Keranocyte

Apoptoc cell

Fig. 1. IFN-a induced apoptosis via TRAIL in the skin in CLE. IFN = interferon. pDC = plasmacytoid dendritic cell. TRAIL = TNF-related apoptosis-inducing ligand.

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[46,47]. The clinical studies of rontalizumab, a humanized immunoglobulin G1 anti-IFN-a monoclonal antibody, found a signicant
decrease in IFN-regulated gene expression in whole blood-derived
RNA, but not in anti-dsDNA antibody levels [48]. The primary endpoint of the phase II study for rontalizumab, the British Isles Lupus
Assessment Group (BILAG) response index, was not signicantly
different between the treatment and placebo groups [49].
Amgens drug AMG 811, an anti-IFN-c monoclonal antibody, is also
currently undergoing clinical trials for the treatment of SLE.

5. Tumor necrosis factor-alpha

5.1. Key points
 TNFa is increased in the serum and skin of CLE patients.
 Keratinocytes produce TNFa in response to UV light and inammatory cytokines, particularly IL-1a, IL-18 and IFN-c.
 In CLE, high levels of TNFa increase the production of inammatory cytokines, chemokines and adhesion molecules, which
recruit inammatory cells into the skin.
 TNFa also activates B cells to produce antibodies and increases
the expression of nuclear antigens on the keratinocyte surface.
 The 308A TNFa promoter polymorphism is associated with
increased production of TNFa in SCLE compared to healthy controls [50].
 Although increased levels of TNFa cause CLE, decreasing levels
of TNFa with a TNFa inhibitor can also produce CLE-like
symptoms.
TNFa is an inammatory cytokine involved in the mechanism of
many autoimmune diseases such as rheumatoid arthritis, psoriasis
and inammatory bowel disease as well as lupus. Both the serum
and skin of CLE patients have high levels of TNFa, which may cause
inammation in LE skin lesions [51,52]. However, the role of TNFa
in CLE is unclear because use of a therapeutic TNFa inhibitor is
associated with the appearance of SCLE-like lesions. TNFa is
involved in cytokine production, B cell regulation and inhibition
of IFN-a production from pDCs. TNFa may have both inammatory
and immunomodulatory roles in CLE (Table 3).
In the skin, keratinocytes, dermal broblasts and mast cells produce TNFa. UV irradiation, IL-1a, IL-18 and IFN-c increase these
cells production of TNFa [42,5356]. Within hours after exposure
to UVB, the keratinocytes, dermal broblasts and mast cells release
TNFa triggering an inammatory cascade and photosensitivity
[55]. This effect of UV on TNFa production is mediated through
the TNFa promoter, which contains four nuclear factor kappa B
(NFjB) binding sites and one activator protein 1 (AP-1) binding
site, both of which are UV-stimulated transcription factors
[57,58]. Studies suggest that AP-1 mediates the UVB effect, while
IL-1 mediates through NFjB a synergistic increase in TNFa production by UVB-irradiated broblasts and keratinocytes [59].
As an inammatory molecule TNFa induces the production of
cytokines, chemokines and adhesion molecules such as IL-1, IL-6,
CXCL8, CCL20, selectins, vascular cell adhesion molecule 1
(VCAM-1) and ICAM-1. The selectins and adhesion molecules
enable leukocyte rolling, attachment and chemotaxis through dermal blood vessels into the skin. In total, these factors create a positive feedback loop for TNFa in which TNFa upregulates its own
production and release from UVB irradiated human keratinocytes.
In addition to the above functions, TNFa activates Langerhans cells
by binding the TNF p75 receptor [60]; acts as a growth factor for B
cells and increases the production of antibodies; acts as a B cell
regulator; and reduces the release of IFN-a from pDCs [61].
Finally, TNFa upregulates the production of 52-kd Ro/SSA mRNA
and protein, the surface expression of Ro/SSA and La/SSB on

Table 3
The role of tumor necrosis factor-a (TNFa) in the pathogenesis of CLE.
CCL = Chemokine (C-C motif) ligand. CLE = Cutaneous lupus erythematosus.
CXCL = Chemokine (CXC motif) ligand. ICAM-1 = Intracellular adhesion molecule 1.
IFN = Interferon. IL = Interleukin. pDC = Plasmacytoid dendritic cell. TNFa = Tumor
necrosis factor-a. VCAM-1 = Vascular cell adhesion molecule 1.
Potential
CLE
pathogenic
factors

Primary
source(s)

Primary function

TNFa

Keratinocytes
Fibroblasts
Mast cells

Proinammatory
and antiinammatory

Primary role(s) in the

pathogenesis of CLE

 Stimulates production of inammatory

cytokines, chemokines and adhesion
molecules such as
IL-1, IL-6, CXCL8,
CCL20, VCAM-1 and
ICAM-1
 Activates B cells antibody production
 Upregulates
keratinocyte
surface
expression of lupus
antibodies
 Reduces the release
of IFN-a from pDCs,
which may cause
TNFa
inhibitor-induced lupus

keratinocytes and the binding of anti-Ro/SSA antibodies to keratinocytes [62,63]. These ndings emphasize multiple potential
roles for TNFa in the pathogenesis of CLE.
Increased levels of TNFa have been found in many studies of
CLE and SLE patients. Refractory skin lesions in SCLE, the most photosensitive type of lupus, are strongly positive for TNFa in the epidermis [52]. The prevalence of the
308A TNFa promoter
polymorphism, which is associated with increased TNFa production, is higher in SCLE compared to healthy controls [50].
Circulating levels of TNFa are elevated in SLE and the levels of
the TNF soluble receptors (TNF-sR) TNF-sR55 and TNF-sR75 correlate with the Systemic Lupus Activity Measure (SLAM) index [64].
One study though had contradictory ndings with increased TNFa
levels in patients with inactive SLE (Systemic Lupus Erythematosus
Disease Activity Index [SLEDAI] 6 2) compared to patients with
very active SLE (SLEDAI P 13) and control patients, possibly suggesting that TNFa is a protective factor in SLE [65].
Despite this evidence for the inuence of increased TNFa in the
pathogenesis of LE, medications that inhibit TNFa and TNFas
actions also induce lupus. One study reported the incidence of
TNFa inhibitor-induced lupus to be 0.93% (25/2682) for iniximab,
0.81% (9/1110) for adalimumab and 0.37% (5/1360) for etanercept
[66]. Anti-TNFa agents can produce a myriad of systemic symptoms
and cutaneous symptoms equivalent to those found in idiopathic LE
such as fever, arthritis and rashes. TNFa inhibitors can also induce
lupus antibodies. Positive anti-dsDNA antibodies were found in
20% of iniximab, 1012% of adalimumab, 15% of etanercept and
4% of certolizumab pegol treated patients who had previously tested negative for anti-dsDNA antibodies [67]. Antiphospholipid antibodies may also be present in TNFa inhibitor-induced lupus. Antihistone antibodies are found in some types of drug-induced lupus,
but are uncommon in TNFa inhibitor-induced lupus.
In cases of TNFa inhibitor-induced lupus, once the offending
TNFa inhibitor causing lupus-like symptoms is stopped the patient
usually improves over days to weeks with antibodies normalizing
over months. Treatment with topical steroids, topical non-steroidal
immunomodulators or oral antimalarials may be needed. Rarely,
systemic steroids or steroid-sparing agents must be used.

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It is unclear if the TNFa inhibitor unmasks underlying lupus or

truly induces lupus. The interaction of TNFa with IFN-a may
explain the mechanism of TNFa inhibitor-induced lupus. TNFa
inhibits the release of IFN-a from pDCs [61]. When endogenous
TNFa is eliminated, as it is with an anti-TNFa agent, pDC production
of IFN-a increases [61]. As previously described, increased IFN-a
triggers an inammatory cascade resulting in tissue inammation.
Interestingly, although TNFa inhibitors are well characterized as
causing lupus-like symptoms, short-term anti-TNF therapy may
improve some manifestations of LE, particularly nephritis [68].
6. Interleukins
6.1. Key points
 Many inammatory interleukins play important roles in the
pathogenesis of CLE.
 Increased levels of IL-6 and IL-10 in CLE may cause B cell
hyperactivity.
 Decreased IL-12 levels in LE enable increased humoral immune
responses and UV-induced keratinocyte apoptosis.
 IL-17 likely contributes to the increased production of inammatory cytokines and chemokines in CLE.
 High levels of IL-18 and the IL-18 receptor in CLE increase TNFa
production, decrease IL-12 production and trigger keratinocyte
death.
 New drugs for CLE and SLE are being developed that act along
the interleukin pathway.
6.2. IL-1
IL-1 is an inammatory cytokine central to the regulation of the
immune system. IL-1 release from keratinocytes is markedly
increased after UV irradiation, and there is a synergistic increase in
TNFa release from keratinocytes and broblasts when IL-1a is added
to UVB-irradiated cells [53]. IL-1 stimulates the production of TNFa
and the inammatory chemokines CCL5, CCL20, CCL22 and CXCL8 in
epidermal keratinocytes [16]. IL-1 is increased in the serum of
patients with SLE and correlates with SLE disease activity [69].
6.3. IL-6 and IL-10
Increased IL-6 and IL-10 in CLE may induce B cell hyperactivity.
IL-6 may have anti- and pro-inammatory functions. IL-6 stimulates B cell maturation and immunoglobulin secretion as well as
cytotoxic T cell production and differentiation. In the skin, UVB
irradiation increases keratinocyte expression of IL-6 mRNA
[70,71]. In SLE, monocytes and B cells also produce IL-6 [72]. IL-6
serum levels are signicantly higher in SLE than in healthy controls, and IL-6 serum levels correlate with the SLEDAI score, erythrocyte sedimentation rate and C-reactive protein level [72,73].
Multiple cells including B cells, monocytes, CD4 + T cells and
CD8 + T cells produce IL-10 [72,73]. IL-10 is largely regarded as
an anti-inammatory cytokine, but may also stimulate B cells. IL10 suppresses Th1 cells, macrophages and dendritic cells as well
as increases B cell proliferation, maturation and immunoglobulin
production. Like IL-6, IL-10 serum levels are increased in SLE and
the IL-10 levels correlate with SLE disease activity and the antidsDNA antibody levels, and negatively with C3, C4 and lymphocyte
counts [7274]. Increased levels of IL-6 and IL-10 in LE, resulting in
B cell hyperactivation, may contribute to the development of CLE.
6.4. IL-12
IL-12 is an anti-inammatory cytokine that is reduced in LE. B
cells, dendritic cells and macrophages produce IL-12. IL-12 is a

331

Th1 cytokine that regulates T lymphocytes via IFN-c, inhibits

humoral immune responses (including the production of antidsDNA antibodies) and protects keratinocytes from UVB- and
TNFa-induced apoptosis [75,76]. In one study, the addition of IL12 to the PBMC of lupus patients reduced IL-10 levels [76]. More
importantly, IL-12 reduced anti-dsDNA antibody production independently from this change to IL-10. An imbalance between IL-12
and IL-10 contributes to the pathogenesis of SLE and potentially to
the pathogenesis of CLE.
6.5. IL-17
IL-17 is increased in lesional LE skin [77]. Th17 cells produce IL17, an inammatory cytokine family consisting of six members, IL17A-F. IL-23 enhances the production of IL-17 [78]. IL-17 stimulates
T cells and increases the production of autoantibodies, inammatory
cytokines (IL-1 and IL-6) and chemokines (CCL2, CCL7, CCL20, CXCL1
and CXCL5) [79,80]. A study of IL-17 levels in the serum and skin of
subjects with SLE (n = 23), DLE (n = 26) and SCLE (n = 17) found higher lesional concentrations of IL-17A and higher IL-17 serum levels in
all lupus groups compared to controls [81]. However, a different
study of seven DLE patients did not nd IL-17 producing Th17 cells
or an increase in IL-17-associated genes in the lesional skin [82]. In
SLE, an increased serum IL-17 level and the number of Th17 cells correlated with a higher SLEDAI score and CXCL10 level [78]. These
results indicate a possible role for IL-17 in the development of
inammation in CLE and SLE.
6.6. IL-18
IL-18, another inammatory cytokine increased in CLE, is a
member of the IL-1 superfamily produced by macrophages and
other immune cells. IL-18 helps immune cells to migrate into tissue, stimulates the production of inammatory cytokines including IFN-c, TNFa and IL-1b, and potentiates IFN-c induced
production of CXCL9, CXCL10 and CXCL11 [83]. IL-18 is increased
in the serum [84,85] and kidney tissue [86] of SLE patients as well
as in CLE keratinocytes [56]. Serum levels of IL-18 correlate with
SLE disease activity [84,85]. A study of hair follicle keratinocytes
from CLE patients had a higher cell surface level of the IL-18 receptor than controls [56]. In this study, the addition of TNFa and IFN-c
further increased keratinocyte surface expression of the IL-18
receptor. The addition of IL-18 to these cells stimulated the keratinocytes to increase TNFa production and inhibit IL-12 production, resulting in keratinocyte death. In total, IL-18s multiple
actions contribute to the inammatory cascade that causes CLE.
6.7. Treatments targeting the interleukin pathways
LE treatments target many of these interleukin pathways
(Table 4). Chloroquine inhibits UVB irradiation-induced production
of IL-1b and IL-6 [71]. Hydroxychloroquine reduces IL-1a production from monocytes and IL-6 production from T cells and monocytes, but does not impact IL-2 or IL-4 [87]. Recent studies of
tocilizumab, an anti-IL-6 receptor antibody currently approved
for the treatment of rheumatoid arthritis, found decreased SLE disease activity in the treatment group as well as success in a case of
refractory CLE [88,89]. A placebo-controlled clinical trial for
sirukumab, a human IL-6 monoclonal antibody, in CLE and SLE
patients found no clinically signicant change in the clinical disease activity scores of the treated patients as measured by the
CLASI, BILAG or safety of estrogen in lupus erythematosus national
assessment (SELENA)-SLEDAI [90]. In another trial, an anti-IL-10
monoclonal antibody decreased cutaneous lesions, joint symptoms
and SLEDAI scores of SLE subjects [91].

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E.S. Robinson, V.P. Werth / Cytokine 73 (2015) 326334

Table 4
The role of interleukin (IL) in the pathogenesis of CLE. CCL = Chemokine (CC motif)
ligand. CD = Cluster of differentiation. CLE = Cutaneous lupus erythematosus.
CXCL = Chemokine (CXC motif) ligand. IFN = Interferon. IL = Interleukin. Th1 = Thelper 1 cell. Th17 = T-helper 17 cell. TNFa = Tumor necrosis factor-a.
UV = Ultraviolet.
Potential
CLE
pathogenic
factors

Primary
source(s)

Primary function

IL-1

Keratinocytes

Proinammatory

IL-6

Keratinocytes

Proinammatory
and antiinammatory

IL-10

B cells
Monocytes
CD4 + T cells
CD8 + T cells

Proinammatory
and antiinammatory

IL-12

B cells
Dendritic
cells
Macrophages

Antiinammatory

IL-17

Th17 cells

Proinammatory

IL-18

Macrophages

Proinammatory

Primary role(s) in the

pathogenesis of CLE

 Amplies production
of TNFa and the
inammatory
chemokines
CCL5,
CCL20, CCL22 and
CXCL8
 Triggers
B
cell
maturation
and
immunoglobulin
secretion
 Increases cytotoxic T
cell production and
differentiation
 Suppresses Th1 cells,
macrophages
and
dendritic cells
 Stimulates
B
cell
hyperactivity
 Regulates
T
cell
function
 Reduces immunoglobulin production
 Protects
keratinocytes from UVinduced apoptosis
 Stimulates T cells
 Increases the production of autoantibodies
 Triggers the production of inammatory
cytokines
and
chemokines including
IL-1, IL-6, CCL2, CCL7,
CCL20, CXCL1 and
CXCL5
 Stimulates the production of the inammatory
cytokines
IFN-c, TNFa and IL-1b
 Potentiates IFN-c-induced production of
CXCL9, CXCL10 and
CXCL11

7. Conclusions
Many studies point to cytokines as important factors in the
pathogenesis of CLE. IFNs, TNFa and ILs all play signicant roles.
The actions and interactions of these cytokines in CLE are complex.
The cytokine pathways are impacted by UV light, genetic and other
environmental factors. They are further complicated in that they
may vary with CLE subtype. Current research is continuing to
expand our knowledge of these pathways and identify potential
targets for the treatment of CLE.

Acknowledgements
This material is supported by the Veterans Health
Administration, Ofce of Research and Development, Biomedical
Laboratory Research and Development and a VA Merit Review grant
to VPW.

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