Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Inactivation of the Transcription Factor STAT4 Prevents Inflammation-Driven Fibrosis in Systemic Sclerosis Animal Models.

Avouac3,  Jerome, Furnrohr2,  Barbara G., Tomcik4,  Michal, Palumbo2,  Katrin, Zerr2,  Pawel, Horn2,  Angelika, Dees2,  Clara

Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Paris Descartes University, Rheumatology A Department, Cochin Hospital, and INSERM U781, Necker Hospital
Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany and Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of the First Faculty of Medicine, Charles U
Friedrich Alexander Univ, Erlangen, Germany
Paris Descartes University, Rheumatology A Department, Cochin Hospital, and INSERM U781, Necker Hospital, Paris, France
University of Erlangen, Erlangen, Germany

Objective:

STAT4 is a transcriptional factor regulating various cytokines and in particular interferon type 1 and IL12-IL23 pathways. STAT4 has been recently identified as a genetic susceptibility factor to systemic sclerosis (SSc) and also to other autoimmune diseases. Our aim was to investigate the contribution of STAT4 in the development of a fibrotic phenotype in two different mouse model of experimental dermal fibrosis.

Methods:

The role of STAT 4 was first evaluated in the mouse model of bleomycin-induced dermal fibrosis, a model for early, inflammatory stages of SSc. Mice deficient for STAT4 (stat4-/-) and wildtype littermates (stat4+/+) were injected with bleomycin or NaCl. Infiltrating leukocytes and T cells in lesional skin of STAT4-/- and STAT4+/+ mice were quantified respectively on hematoxylin and eosin stained sections and by immunohistochemistry for CD3. Th1 and Th2 cytokine levels were also measured in the serum or lesional skin samples of stat4-/- and stat4+/+ mice. The invalidation of STAT4 was also investigated in the tight-skin (tsk-1) mouse model, which serve as a model of later, less inflammatory stages of SSc.

Results:

stat4-/- mice were protected from bleomycin-induced dermal fibrosis with reduced dermal thickening (65±3% reduction, p=0.03), hydroxyproline content (68±5% decrease, p=0.02) and myofibroblast counts (71±6% reduction, p=0.05). The numbers of leukocytes, especially infiltrating T cells, were also decreased in lesional skin of stat4-/- mice (respectively 62±4%, p=0.02 and 63±5%, p=0.02). Moreover, stat4-/- mice displayed in lesional skin decreased levels of cytokines involved in inflammatory and fibrotic processes such as IL-6 (50±4% decrease), TNFa (71±5%), INFg (58±3%) and IL-2 (63±4%). Similar results were observed in the serum.

Consistent with a primary role of STAT4 on inflammation, STAT4 deficiency did not improve the fibrotic phenotype in tsk-1 mice. No differences in hypodermal thickness, hydroxyproline content and myofibroblasts counts were observed between stat4-/-/tsk-1 mice and their stat4+/+/tsk-1 littermates.

Conclusion:

This is the first translational study demonstrating the role of the transcription factor STAT4, an established genetic susceptibility factor of SSc and different autoimmune diseases, in animal models of SSc. We herein demonstrate that STAT4 exerts potent profibrotic effects in inflammation-driven models of fibrosis. STAT4 indirectly regulates the activation of fibroblasts by promoting the infiltration of T cells into lesional skin and the production of inflammatory cytokines. These findings confirm the results of the genetic studies on the role of STAT4 in the development of SSc.

To cite this abstract, please use the following information:
Avouac, Jerome, Furnrohr, Barbara G., Tomcik, Michal, Palumbo, Katrin, Zerr, Pawel, Horn, Angelika, et al; Inactivation of the Transcription Factor STAT4 Prevents Inflammation-Driven Fibrosis in Systemic Sclerosis Animal Models. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :607
DOI: 10.1002/art.28375

Abstract Supplement

Meeting Menu

2010 ACR/ARHP