Increased expression of guanylate binding protein-1 in lesional skin of patients with cutaneous lupus erythematosus

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DOI: 10.1111/j.1600-0625.2010.01160.x · Source: PubMed
Abstract
The large GTPase human guanylate binding protein-1 (GBP-1) is a key mediator of angiostatic effects of inflammation and is induced by interferon (IFN)-α and IFN-γ in endothelial cells (ECs). The aim of this study was to investigate whether GBP-1 is a marker of skin lesions in patients with cutaneous lupus erythematosus (CLE). Western blotting revealed that GBP-1 was in vitro induced by IFN-α and -γ in primary keratinocytes obtained from healthy controls. Moreover, we found that this protein was expressed by keratinocytes and ECs in primary and ultraviolet (UV)-induced skin lesions from patients with various subtypes of CLE, when compared to non-lesional skin. No GBP-1 expression was noted in skin biopsy specimens 24 or 72 h after UV irradiation prior to lesion formation in patients with CLE or in healthy control specimens with or without UV irradiation. Initial findings suggest that GBP-1 is not expressed in other skin diseases with different inflammatory aetiology, such as atopic dermatitis. We conclude that GBP-1 expression is closely associated with skin lesions in patients with CLE, suggesting a contribution of GBP-1 in the pathogenesis of this disease.
Increased expression of guanylate binding protein-1 in lesional skin
of patients with cutaneous lupus erythematosus
Elisabeth Naschberger
1
,Jo¨ rg Wenzel
2
, Cosima C. Kretz
3
, Martin Herrmann
4
, Michael Stu
¨
rzl
1
and Annegret Kuhn
3,5
1
Division of Molecular and Experimental Surgery, University Medical Center Erlangen, Erlangen, Germany;
2
Department of Dermatology,
University of Bonn, Bonn, Germany;
3
Tumor Immunology Program, Division of Immunogenetics, German Cancer Research Center, Heidelberg,
Germany;
4
Institute for Clinical Immunology, Department of Internal Medicine III, University Medical Center Erlangen, Erlangen, Germany;
5
Department of Dermatology, University of Muenster, Muenster, Germany
Correspondence: Dr Elisabeth Naschberger, Division of Molecular and Experimental Surgery, University Medical Center Erlangen, Schwabachanlage
10, D-91054 Erlangen, Germany, Tel: +49-9131-85-39141, Fax: +49-9131-85-32077, e-mail: elisabeth.naschberger@uk-erlangen.de
Abstract: The large GTPase human guanylate binding protein-1
(GBP-1) is a key mediator of angiostatic effects of inflammation
and is induced by interferon (IFN)-a and IFN-c in endothelial
cells (ECs). The aim of this study was to investigate whether GBP-
1 is a marker of skin lesions in patients with cutaneous lupus
erythematosus (CLE). Western blotting revealed that GBP-1 was
in vitro induced by IFN-a and -c in primary keratinocytes
obtained from healthy controls. Moreover, we found that this
protein was expressed by keratinocytes and ECs in primary and
ultraviolet (UV)-induced skin lesions from patients with various
subtypes of CLE, when compared to non-lesional skin. No GBP-1
expression was noted in skin biopsy specimens 24 or 72 h after
UV irradiation prior to lesion formation in patients with CLE or
in healthy control specimens with or without UV irradiation.
Initial findings suggest that GBP-1 is not expressed in other skin
diseases with different inflammatory aetiology, such as atopic
dermatitis. We conclude that GBP-1 expression is closely
associated with skin lesions in patients with CLE, suggesting a
contribution of GBP-1 in the pathogenesis of this disease.
Key words: guanylate binding protein inflammation interferon
lupus erythematosus skin UV light
Accepted for publication 21 June 2010
Introduction
Lupus erythematosus (LE) is a chronic inflammatory autoimmune
disease with heterogeneous clinical presentation. In contrast to the
multi-organ disease of systemic LE (SLE), the manifestations of
cutaneous LE (CLE) are primarily confined to the skin. Clinical
manifestation of CLE varies widely, making it necessary to classify
different subtypes of the disease, such as acute CLE (ACLE), sub-
acute CLE (SCLE), chronic CLE (CCLE), and intermittent CLE
(ICLE) (1). CCLE is further subdivided into discoid lupus erythe-
matosus (DLE), lupus erythematosus panniculitis (LEP), and chil-
blain lupus erythematosus (CHLE). The complexity of these
subtypes hampers understanding of the underlying pathological
mechanisms, in addition to implying a multifactorial pathogenic
course.
Recent studies have further demonstrated that type I interferons
(IFNs), such as IFN-a and -b, play an important role in the path-
ogenesis of CLE (2). Interestingly, strong expression of myxovirus
protein A (MxA), a protein specifically induced by type I IFNs,
has been observed in lesional skin of patients with CLE, along
with large numbers of infiltrating CXCR3
+
lymphocytes (3). Natu-
ral IFN-a-producing cells, also termed plasmacytoid dendritic cells
(pDCs), have been detected in CLE lesions (4,5) and are associ-
ated with the presence of MxA (3). These findings suggest that
local IFN-a production by pDCs promotes T-helper 1 (Th1)-
biased inflammation. In addition, Wenzel et al. (6) showed that
the expression pattern of IFN-inducible proteins reflects the histo-
logical distribution of infiltrating immune cells in different sub-
types of CLE. These results demonstrate a close morphological
association between IFN-inducible protein expression and the dis-
tribution of CXCR3
+
lymphocytes, supporting the importance of
IFN-driven inflammation in CLE (7).
Among the proteins most abundantly induced by IFNs in eukary-
otic cells is guanylate binding protein-1 (GBP-1) (8). GBP-1 belongs
to the large GTPase family, which consists of seven homologous
members (9–11). GBP-1 is expressed by endothelial cells (ECs)
exposed to IFN-a and -c, interleukin (IL)-1a and -1b, and TNF-a
both in vitro and in vivo (12,13) and mediates these proteins’ potent
anti-angiogenic effects (14–16). GBP-1 has been identified as a
marker of the proinflammatory microenvironment dominated by
these cytokines during such inflammation-associated skin diseases
as psoriasis and Kaposi’s sarcoma, as well as during adverse drug
reactions (13). GBP-1 also inhibits EC proliferation and invasiveness
(14,15) as well as the ability of ECs to spread and migrate (16), thus
mediating the anti-angiogenic effects of inflammatory cytokines.
Interestingly, the protein is secreted from cytokine-activated ECs,
suggesting in addition an extracellular function which has to be
determined (17). Recently, GBP-1 was found to be expressed in
32% of patients suffering from colorectal carcinoma and was corre-
lated with improved cancer-related survival (18). In these patients,
GBP-1 expression was associated with an IFN-dependent, Th1-like
anti-angiogenic microenvironment.
To investigate the role of GBP-1 in CLE, we analysed its expres-
sion in tissues of patients suffering from various disease subtypes.
Lesional and non-lesional skin biopsies from the same patients
with CLE were studied, as well as skin biopsies from patients
undergoing ultraviolet light (UV) light exposure. Additionally, the
expression levels were compared with those of healthy controls
and patients suffering from other skin diseases. Moreover, the
DOI:10.1111/j.1600-0625.2010.01160.x
www.blackwellpublishing.com/EXD
Original Article
102 ª 2011 John Wiley & Sons A/S, Experimental Dermatology, 20, 102–106
expression of other IFN-dependent proteins, such as MxA,
CXCL9, and CXCL10, was analysed to identify potential coregula-
tion with GBP-1.
Methods
Patients and skin biopsies
The diagnosis and classification of CLE were based on clinical and
histopathological criteria as well as on serologic abnormalities
according to the Duesseldorf Classification 2004 (1). In total, thirty-
eight patients with CLE were included in the study: SCLE, five men
and four women, 48.4 ± 19.5 years; DLE, nine men and five
women, 48.4 ± 13.5 years; and lupus erythematosus tumidus
(LET), seven men and eight women, 48.1 ± 17.0 years. None of
these patients fulfilled four or more criteria of the American College
of Rheumatology (ACR) for the classification of SLE at the time of
analysis (19). Skin biopsy specimens were collected from primary
skin lesions (e.g. face, chest, arms, back abdomen) of 31 patients
with different stages of the disease (e.g. early acute, fully developed,
and late chronic lesions), from fully developed skin lesions induced
by UVB irradiation (1.5 minimal erythema dose [MED]) of five
patients, and from non-lesional skin of nine patients with CLE. We
also analysed skin biopsy specimens from two patients with CLE 24
and 72 h after a single dose of a combined UVA (60–100 J cm
2
)
and UVB (1.5 MED) irradiation. For control purposes, skin biopsies
from one untreated healthy control were examined 24 and 72 h
after a single dose of UVA (60–100 J cm
2
) and UVB (1.5 MED)
irradiation (Data S1). As a control, we also investigated skin biopsy
specimens from five patients with atopic dermatitis (AD, three men
and two women , 55.4 ± 26.5 years) as well as from 13 healthy con-
trols. The ethics committee of the University of Heidelberg, Ger-
many, approved the study, and it was conducted according to the
ethical guidelines of our institution and the Helsinki Declaration.
Immunohistochemistry and evaluation
Staining of paraformaldehyde-fixed, paraffin-embedded tissue sec-
tions for GBP-1 was performed as previously described (13,14,18).
In addition, MxA was used as a marker for type I IFN signalling
(M143, 1:100; Prof. Otto Haller, University of Freiburg, Freiburg,
Germany). Additionally, we analysed the lesional expression of the
IFN-inducible chemokines CXCL9 Mig (MAB392; R&D Systems,
Minneapolis, MN, USA) and CXCL10 IP10 (Clone 33036; R&D
Systems), as well as their common receptor, CXCR3 (1C6, 1:100;
PharMingen, San Diego, CA, USA). The expression of MxA,
CXCL9, and CXCL10 was scored, respectively (0 = no expression;
+ = weak expression; ++ = moderate expression; +++ = strong
expression), as previously described (3). Lymphocyte populations
were counted per three high-power fields (magnification ·200)
and the mean population was calculated.
Further details from the methodology such as provocative
phototesting, isolation of primary keratinocytes, and stimulation
with cytokines as well as Western Blotting are included in the sup-
plementary material (Data S1).
Results
GBP-1 expression is upregulated in all CLE
subtypes but not in atopic dermatitis or healthy
controls
Guanylate binding protein-1 expression in punch biopsies from
skin of patients with SCLE (n = 6), DLE (n = 11), LET (n = 5),
atopic dermatitis (n = 5), and healthy controls (n = 13) was
investigated using a well characterized rat monoclonal antibody
against human GBP-1 (13) (
Fig. 1; Table 1). GBP-1 expression
was increased in more than 95% of all patients with CLE
(Table 1) and was associated with epithelial (Fig. 1a, arrowheads),
endothelial (Fig. 1a, arrows), and infiltrating (Fig. 1a, open
arrows; Table 1) cells. There was no difference in the expression
of GBP-1 with regard to the stage of the disease (e.g. early acute,
fully developed, and late chronic lesions) and the site of localiza-
tion (e.g. face, chest, arms, back abdomen). In contrast, however,
GBP-1 expression was absent from tissues of patients with atopic
dermatitis or healthy controls (Fig. 1b; Table 1). In contrast, stain-
ing controls (isotype control or without primary antibody) were
performed and yielded negative results (data not shown).
GBP-1 is expressed in lesional but not in
non-lesional skin of patients with CLE and can be
induced by IFNs in primary keratinocytes
Three pairs of lesional and non-lesional skin from patients of each
CLE subtype (SCLE, DLE, and LET) were analysed for GBP-1
expression. GBP-1 was found to be expressed in all cases of lesion-
Table 1. GBP-1 is upregulated in all CLE subtypes and is absent in atopic
dermatitis and healthy controls
Disease
Skin
biopsies
(n)
GBP-1
expression
(n)
Positive
cell
types
1
Subacute cutaneous lupus
erythematosus (SCLE)
6 6 EP, EC, IF
Discoid lupus erythematosus (DLE) 11 10 EP, EC, IF
Lupus erythematosus tumidus (LET) 5 5 EP, EC, IF
Atopic dermatitis 5 0
Healthy controls 13 0
1
epithelial cell (EP), endothelial cell (EC), infiltrate (IF)
(a)
(b)
Figure 1. Guanylate binding protein (GBP)-1 expression is upregulated in all CLE
subtypes but not in atopic dermatitis or healthy skin. Tissue sections from patients
with (a) subacute cutaneous lupus erythematosus (SCLE, n = 6), discoid lupus
erythematosus (DLE, n = 11), lupus erythematosus tumidus (LET, n = 5), and (b)
atopic dermatitis (n = 5), as well as healthy controls (n = 13) were stained using a
specific rat anti-human GBP-1 monoclonal antibody (clone 1B1). Brown colour
indicates GBP-1 expression (arrows), while nuclei were counterstained with
haematoxylin and are displayed in blue. Epithelial cells are indicated by
arrowheads, endothelial cells by solid arrows, and infiltrating cells by open arrows.
Scale bars = (a) 100 lm, (b) 250 lm.
Expression of GBP-1 in lesional CLE
ª 2011 John Wiley & Sons A/S, Experimental Dermatology, 20, 102–106 103
al skin (n =9; Fig. 2a; Table 2), while it was not expressed in
non-lesional skin (n = 9) of the same patients (Fig. 2a, non-
lesional; Table 2). The GBP-1-positive cell types in the lesional
skin were epithelial (Fig. 2a, arrowheads), endothelial (Fig. 2a,
arrows), and infiltrating (Fig. 2a, open arrows) cells, which were
most likely monocytes macrophages (Table 2).
To analyse whether IFN-a and -c are inducers of GBP-1, pri-
mary keratinocytes from healthy controls were stimulated for
24 h with 1000 U ml IFN-a or 100 U ml IFN-c. These IFN
concentrations were previously described as the maximal doses
required to induce GBP-1 expression (13). In Western blotting,
GBP-1 was found to be induced by both cytokines (Fig. 2b).
Notably, GBP-1 induction by IFN-c was more pronounced than
that by IFN-a.
GBP-1 expression is induced in fully developed
UV-induced lesions of patients with CLE but not
prior to lesion formation
A photoprovocation test was performed to analyse whether GBP-
1 expression is induced by UV exposure. Five patients with CLE
were irradiated by UVB light according to a standardized proto-
col, and punch biopsies of skin were collected before and after
formation of characteristic CLE lesions. GBP-1 expression was
detected only in fully developed skin lesions of these patients,
while expression was absent in skin biopsies both 24 and 72 h
after UV irradiation prior to lesion formation (Fig. 2c;
Table 3).
Moreover, the protein was not expressed in healthy control spec-
imens 24 or 72 h after UV irradiation (data not shown). This
finding suggests that GBP-1 is only expressed in the fully devel-
oped lesions of patients with CLE and is not induced by UV
irradiation in healthy controls or prior to lesion formation in
patients with CLE.
GBP-1 expression is coregulated with other
IFN-dependent proteins, such as MxA, CXCL9,
and CXCL10
Finally, we investigated whether GBP-1 expression correlates
with the increased expression of other IFN-dependent genes in
patients with CLE. Five consecutive skin sections obtained from
patients with CLE (n = 6) were stained for GBP-1, MxA,
CXCL9, and CXCL10 expression. In addition, the expression of
the CXCL9 and CXCL10 chemokine receptor, CXCR3, was anal-
ysed. GBP-1 was found to be expressed in the same tissue areas
as MxA, CXCL9, and CXCL10 (
Fig. 3). However, the cell types
expressing GBP-1 partly differed from those expressing the
other IFN-regulated genes. For example, GBP-1 is detected in
(a)
(b)
(c)
Figure 2. Guanylate binding protein (GBP)-1 is expressed in primary skin lesions
and in fully developed UV-induced skin lesions of patients with CLE but not prior
to lesion formation after UV irradiation. (a) Lesional and non-lesional skin of
patients with subacute cutaneous lupus erythematosus (SCLE, n = 3), discoid lupus
erythematosus (DLE, n = 3), and lupus erythematosus tumidus (LET, n = 3) was
stained using a specific rat anti-human GBP-1 monoclonal antibody (1B1). Brown
colour indicates GBP-1 expression (arrows), while nuclei were counterstained with
haematoxylin and are displayed in blue. Epithelial cells are marked by arrowheads,
endothelial cells by solid arrows, and infiltrating cells by open arrows. Scale
bar = 100 lm. (b) Primary keratinocytes were isolated from healthy human donors
and were either left untreated or stimulated for 24 h with 1000 U ml IFN-a or
100 U ml IFN-c. Protein extracts were then isolated from these cells and Western
blotting using a specific anti-human GBP-1 antibody (1B1) was performed. Tubulin
was also blotted to demonstrate equal protein loading. (c) Specimens from the UV-
induced, fully developed skin lesions (n = 5), and UV-irradiated skin prior to lesion
formation (n = 4) of patients with CLE , as well as specimens from healthy controls
that were irradiated with UV (n = 2, data not shown), were stained using a specific
rat anti-human GBP-1 monoclonal antibody (1B1). Brown colour indicates GBP-1
expression (arrows), while nuclei were counterstained with haematoxylin and are
displayed in blue. Scale bar = 250 lm.
Table 2. Guanylate binding protein (GBP)-1 expression is associated with
lesional skin in patients with CLE
Disease subtype
GBP-1 expression
Positive
cell types
1
Lesional
(n =3)
Non-lesional
(n =3)
Subacute cutaneous
lupus erythematosus (SCLE)
3 0 EP, EC, IF
Discoid lupus erythematosus (DLE) 3 0 EP, EC, IF
Lupus erythematosus tumidus (LET) 3 0 EP, EC, IF
1
epithelial cell (EP), endothelial cell (EC), infiltrate (IF)
Table 3. Guanylate binding protein (GBP)-1 expression is induced in fully
developed lesions of patients with CLE after UV irradiation
Disease subtype
Skin
biopsies
(n)
GBP-1
expression
after UV
irradiation (n)
Positive
cell types
1
UV-induced CLE skin lesions 5 4 EP, EC, IF
Prelesional UV-irradiated
skin of patients with CLE
40
UV-irradiated skin of healthy
controls
20
1
epithelial cell (EP), endothelial cell (EC), infiltrate (IF)
Naschberger et al.
104 ª 2011 John Wiley & Sons A/S, Experimental Dermatology, 20, 102–106
epithelial cells, endothelial cells, and infiltrate, whereas CXCL9
is expressed by epithelial cells only. The strongest coregulation
of expression was detected for GBP-1 and MxA, both expressed
in epithelial cells, endothelial cells, and infiltrate. CXCR3 was
also present in the same regions of the tissue. In addition, the
level of GBP-1 expression was correlated with the degree of
lesional inflammation.
Discussion
CLE is a chronic autoimmune disease characterized by skin
inflammation. Recent studies have demonstrated that type I IFNs,
such as IFN-a, play a crucial role in the pathogenesis of the
disease. Here, we investigated the expression and function of
GBP-1, one of the major IFN-inducible proteins in eukaryotic
cells. The expression of this IFN-dependent large GTPase was
analysed in skin biopsy specimens obtained from patients with dif-
ferent subtypes of CLE. Specimens collected after UV exposure, as
well as biopsies from healthy controls, were also analyse d. We
observed that (i) GBP-1 was upregulated in all investigated CLE
subtypes and (ii) its expression was solely detectable in the lesional
skin of these patients. Moreover, (iii) GBP-1 was also present in
fully developed UV-induced lesions but was not expressed after
UV exposure or prior to lesion formation. In addition, (iv) the
protein was not detected in skin biopsies obtained from healthy
controls with or without UV irradiation or from patients with
other skin diseases with different inflammatory aetiology, such as
atopic dermatitis.
Moreover, the presence of type I IFNs, such as IFN-a, in skin
lesions of patients with CLE has been well described and is known
to encourage progression of this autoimmune disease (3,20–23).
In contrast to CLE, acute lesions of atopic dermatitis of adult
patients are characterized by elevated levels of Th2 cytokines and
low levels of TNF-a, IL-1b, and IFN-c (24,25). Moreover, GBP-1
expression is selectively upregulated by IFN-a and -c, TNF-a,
and or IL-1a and -1b and is not induced by any other chemokine
(MCP-1, MIP-1b, PF-4, CXCL10 IP-10, SDF-1a), angiogenic
growth factor (VEGF, bFGF, angiopoietin-2, PDGF-B B), or cyto-
kine (IL-4, -6, -10, -18, oncostatin M) tested so far (13). There-
fore, our data are consistent with the fact that GBP-1 expression
is absent in the skin of atopic dermatitis and healthy patients. The
increased expression of GBP-1 in skin lesions of patients with CLE
indicates that a specific inflammatory microenvironment may be
present in the disease, characterized by increased levels of IFNs,
TNF-a, and or IL-1. These proinflammatory cytokines are known
to activate ECs, suggesting that the vascular system is involved in
CLE. However, it is still to be determined whether GBP-1 is not
only a marker of activation of these cells but also plays a regula-
tory role in CLE.
Interestingly, GBP-1-positive cell types in CLE included ECs,
infiltrating cells, and skin epithelial cells, such as keratinocytes. A
high association of GBP-1 with ECs and infiltrating cells in vivo
has been shown previously (13,14), but this is the first report of
association with skin epithelial cells. It has been described that
pDCs are the major cellular source of IFNs in CLE and accumu-
late in high amounts in the skin of patients with the disease (4).
Therefore, the epithelial cells in the skin of patients with CLE are
likely constantly exposed to this highly IFN-dominated microenvi-
ronment, which in turn may trigger the upregulation of GBP-1 in
these cells.
Moreover, it has been demonstrated that UVB irradiation of
primary human keratinocytes in the presence of proinflammato-
ry cytokines, such as IL-1 (26), TNF-a (27), and IFN-c, signifi-
cantly enhances the expression of the chemokines CCL5,
CCL20, CCL22, and CXCL8 (28). In addition, the CXCR3
ligands CXCL9, CXCL10, and CXCL11 have been identified as
the most abundantly expressed genes in patients with CLE
(2,6). In the present study, GBP-1 was found to be coexpressed
with other IFN-dependent genes, such as MxA and the antian-
giogenic chemokines CXCL9 and CXCL10. Notably, MxA
expression is mainly IFN-a-dependent (29), whereas CXCL9 and
CXCL10 can be induced by either IFN-a or -c, similar to
GBP-1 (30,31). In addition, the CXCL9 and CXCL10 chemokine
receptor CXCR3 (32) was coexpressed in areas of GBP-1
CXCL9 CXCL10 expression. CXCL9 and CXCL10 are not only
the most abundantly expressed genes in patients with CLE but
are also well characterized as anti-angiogenic chemokines in
diseases such as metastatic renal cell carcinoma (33,34). In colo-
rectal carcinoma, the coregulation of GBP-1 with CXCL9 and
CXCL10 has been described (18). Interestingly, GBP-1-positive
patients were characterized by an increased cancer-related sur-
vival of 16.2% and a reduced relative risk of cancer-related
death by 50% when compared to GBP-1-negative patients. It
was further demonstrated that in colorectal carcinoma with high
GBP-1 expression, angiogenesis was reduced (18). This suggests
that during high GBP-1 CXCL9 CXCL10 expression, angiogene-
sis might be reduced in the skin of patients with CLE as
GBP-1 was also found to be associated with endothelial cells
in the disease. In addition, the reduced angiogenesis may be at
least partially caused by reduced neovascularization. The func-
tional role of GBP-1 expression in epithelial cells remains to be
determined.
The exclusive expression of GBP-1 in the genuine and fully
developed UV-induced skin lesions of patients with CLE sug-
gests that GBP-1 may play an important role in disease patho-
genesis. It has to be determined whether GBP-1 can be used as
a diagnostic marker or as a promising target for therapeutic
intervention.
Figure 3. Guanylate binding protein (GBP)-1 expression is coregulated with other
IFN-dependent proteins, such as MxA, CXCL9, and CXCL10, in patients with CLE.
Lesional skin biopsy specimens from patients with CLE (n = 6) were stained for
GBP-1, MxA, CXCL9, CXCL10, and CXCR3 using specific antibodies. Brown colour
indicates GBP-1 expression while MxA, CXCL9, CXCL10, and CXCR3 expression is
indicated by pink colour. The nuclei were counterstained using haematoxylin and
are displayed in blue. Scale bar = 250 lm. GBP-1 expression and the inflammatory
infiltrate was scored semi-quantitatively (no expression > weak expression > fair
expression > strong expression).
Expression of GBP-1 in lesional CLE
ª 2011 John Wiley & Sons A/S, Experimental Dermatology, 20, 102–106 105
Acknowledgements
We thank Melanie Nurtsch, Division of Molecular and Experimental Sur-
gery, University Medical Center Erlangen, and Christine Stumpf, Tumor
Immunology Program, Division of Immunogenetics, German Cancer
Research Center, for excellent technical assistance. We are also grateful to
the Departments of Dermatology, University of Heidelberg, and University
of Duesseldorf, Germany, for providing the skin tissue samples.
Funding
This work was supported by grants from the Interdisciplinary Center for
Clinical Research (IZKF) of the University Medical Center Erlangen to MH
(TP A25) and EN MS (TP D8), a Heisenberg Scholarship awarded to AK
by the German Research Foundation (KU 1559 1-2), and grants awarded
by the German Research Foundation to JW (WE-4428 1-1), MH (HE
4490 3-1) and MS (STU 317 2-1).
Authors’ Contributions
AK, EN, MH and MS designed research; AK, CK, EN and JW performed
experiments; AK, EN, JW, MH and MS analysed data; AK, EN and JW
prepared the manuscript. The final manuscript was approved by all
authors.
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    • " , 2008 ) . These activities have been linked to the ability of IFNs to phosphorylate STAT1 ( Zitzmann et al . , 2006 ) . High expression of ISGs such as CXCL9 , CXCL10 , MxA and GBP - 1 has been reported in interface dermatitis conditions such as cutaneous lupus erythematosus ( CLE ) and here increased expression is linked with disease severity ( Naschberger et al . , 2010 ; Wenzel et al . , 2005 ) ."
    [Show abstract] [Hide abstract] ABSTRACT: Interferon lambda (IFNλ) is important for epidermal defence against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN. Herein we report findings revealing cell type-specific differences in IFNλ signalling and function in skin resident cells. In dermal fibroblasts, IFNλ induced the expression of MxA, a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFNλ did not phosphorylate STAT1 in fibroblasts, but instead activated MAPKs. Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFNλ inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFNλ upregulated the expression of TGFβ1-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFNλ. Our study shows cutaneous cell type-specific IFN signalling and suggests that IFNλ, whilst important for epidermal anti-viral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.Journal of Investigative Dermatologyaccepted article preview online, 19 August 2015. doi:10.1038/jid.2015.317.
    Article · Aug 2015
    • "GBP1 has been detected in CLE lesions but not healthy skin. However, it is unknown whether GBP1 is merely a marker of inflammation or plays a role in CLE lesion formation and perpetuation [41]. Glycosaminoglycans (GAGs) have been implicated in CLE. "
    [Show abstract] [Hide abstract] ABSTRACT: The pathophysiology of cutaneous lupus erythematosus (CLE) encompasses the complex interactions between genetics, the environment, and cells and their products. Recent data have provided enhanced understanding of these interactions and the mechanism by which they cause disease. A number of candidate genes have been identified which increase the risk of developing CLE. Ultraviolet radiation, the predominant environmental exposure associated with CLE, appears to initiate CLE lesion formation by inducing apoptosis, precipitating autoantigen presentation, and promoting cellular production of specific cytokines. Autoantibodies are a well-known entity in CLE, but their exact role remains unclear. Finally, cells ranging from native skin cells to innate and adaptive immune cells produce cytokines and other molecules and play specific roles in lesion formation and perpetuation. Native skin cells implicated in CLE include keratinocytes and endothelial cells. Innate immune cells crucial to CLE pathophysiology include dendritic cells and neutrophils. The primary adaptive immune cells thought to be involved include Th1 cells, Th17 cells, cytotoxic T cells, and invariant natural killer T cells. Though the pathophysiology of CLE has yet to be fully characterized, current research provides direction for future research and therapies.
    Full-text · Article · Aug 2015
    • "In accord with the proposed mechanism, inhibitors of TLR7 and TLR9 signaling in a lupus-prone murine model of interface dermatitis attenuated the skin lesions [88]. Moreover, a recently identified IFNα-and γ-induced protein—the GTPase human guanylate binding protein- 1 (GBP-1)—is expressed by keratinocytes and endothelial cells in primary and ultraviolet-(UV-) induced skin lesions from patients with various subtypes of CLE compared to nonlesional skin [89] . It has also been recently demonstrated that the IFNα-inducible IFI16 protein—normally localized in the nucleus—translocates in the cytoplasm of affected skin cells from lupus patients and in UV irradiated keratinocytes—leading to generation of antibodies against the IFNα-inducible IFI16 recently detected in sera of lupus patients [90]. "
    [Show abstract] [Hide abstract] ABSTRACT: Growing evidence over the last few years suggests a central role of type I IFN pathway in the pathogenesis of systemic autoimmune disorders. Data from clinical and genetic studies in patients with systemic lupus erythematosus (SLE) and lupus-prone mouse models, indicates that the type I interferon system may play a pivotal role in the pathogenesis of several lupus and associated clinical features, such as nephritis, neuropsychiatric and cutaneous lupus, premature atherosclerosis as well as lupus-specific autoantibodies particularly against ribonucleoproteins. In the current paper, our aim is to summarize the latest findings supporting the association of type I IFN pathway with specific clinical manifestations in the setting of SLE providing insights on the potential use of type I IFN as a therapeutic target.
    Full-text · Article · Nov 2011
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