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Title

Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4

Authors
Goffin, Laurence
Rezzonico, Roger
Cozzi, Franco
Meroni, Pier Luigi
Published in Arthritis and Rheumatism. 2008, vol. 58, no. 12, p. 3913-23
Abstract OBJECTIVE: Previous studies have revealed the presence of IgG antifibroblast antibodies (AFAs) capable of binding to the surface of fibroblasts in systemic sclerosis (SSc) sera. Since chemokines may directly or indirectly affect the development of fibrosis, this study was undertaken to investigate the production of chemokines induced by AFAs in fibroblasts, and to characterize the signaling pathways and surface molecules involved. METHODS: AFA-positive and AFA-negative IgG were tested on fibroblasts. Chemokine messenger RNA expression was screened by microarray and quantitative reverse transcription-polymerase chain reaction. Production of CCL2, CXCL8, and CXCL10 proteins was assessed by enzyme-linked immunosorbent assay. Pharmacologic inhibitors were used to study signal transduction, with results assessed by Western blotting and immunofluorescence analysis. Fibroblasts with defective expression of Toll-like receptors (TLRs) and anti-TLR monoclonal antibodies (mAb) were used to assess AFA specificity. RESULTS: In human fibroblasts, AFA-positive IgG induced the preferential transcription of chemokines with profibrotic and proangiogenic potential, including, but not exclusively, CCL2, CXCL1, CXCL8, CKLF, and ECGF1, which were distinctly different from those induced by interferon-gamma. Levels of CCL2 and CXCL8 proteins were increased in AFA-stimulated fibroblast culture supernatants. AFA binding to fibroblasts resulted in concomitant activation of ERK-1/2, c-Jun, and NF-kappaB. CCL2 production was sensitive to inhibition of both proteasome and JNK, while CXCL8 production was sensitive only to inhibition of proteasome. AFAs failed to up-regulate CCL2 expression in TLR-4-deficient fibroblasts but not in TLR-6- or TLR-2-deficient fibroblasts. Moreover, anti-TLR-4 mAb, but not anti-TLR-2 mAb, partially inhibited the production of CCL2 induced by AFAs in human fibroblasts. CONCLUSION: Autoantibodies that bind to the surface of fibroblasts may contribute to the pathogenesis of SSc by up-regulating the fibroblast production of profibrotic and proangiogenic chemokines, in a proteasome- and TLR-4-dependent manner.
Keywords AdultAntibodies, Monoclonal/immunologyAutoantibodies/bloodCells, CulturedChemokine CCL2/geneticsChemokine CXCL10/geneticsChemokines/geneticsDermis/cytologyFemaleFibroblasts/immunology/pathologyFibrosisHumansImmunoglobulin G/bloodInterleukin-8/geneticsMaleMiddle AgedRNA, Messenger/metabolismScleroderma, Systemic/immunology/metabolism/pathologySignal Transduction/immunologyToll-Like Receptor 4/immunology/metabolismTranscriptional Activation/immunology
Stable URL https://archive-ouverte.unige.ch/unige:1269
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Identifiers
PMID: 19035500
Structures
Research group La matrice extracellulaire (651)

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Deposited on : 2009-03-31

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