ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1065

Hypoxia-Inducible Factor-1α: Trigger of Toll-Like Receptor Signalling-Engaged Inflammation in Rheumatoid Arthritis

Fanlei Hu1, Rong Mu1, Jiaxin Zhu1, Wenwei Shao2, Lianjie Shi1, Philip L. Cohen3, Xiaoyan Qiu2 and Zhanguo Li1, 1Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China, 2Department of Immunology, School of Basic Medical Science, Peking University, Beijing, China, 3Rheumatology, Temple University, Philadelphia, PA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Innate Immunity and Rheumatic Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Hyperplasia of synovial fibroblasts, infiltration with lymphocytes, and tissue hypoxia are the major characteristics of rheumatoid arthritis (RA). Data has confirmed the central role of toll-like receptors (TLRs) in RA. However, much remains unknown regarding the impact of hypoxia on TLR signalling-induced inflammatory response in RA. The aim of this study was to reveal the effect of hypoxia and its regulator hypoxia-inducible factor-1α (HIF-1α) on the inflammatory response in rheumatoid arthritis synovial fibroblast (RASF) upon the recognition of pathogen molecules. 

Methods:

Hypoxia was induced in RASF by incubation with Na2S2O4. TLR3 ligand polyIC, TLR2 ligand PGN, TLR4 ligand LPS, and TLR9 ligand CpG were used to stimulate the cells. Effects of hypoxia on these ligands-induced inflammatory cytokines and matrix metalloproteinases (MMPs) were determined by RT-PCR, realtime PCR, and ELISA. Overexpressing HIF-1α as well as knocking-down its expression by siRNA were used to reveal its fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry, realtime PCR, and ELISA analyses after RASF/T cell coculture.

Results:

Hypoxia potentiated the expression of inflammatory cytokines, MMPs, and VEGF in RASF stimulated by different TLR ligands, especially polyIC, a synthetic mimic of dsRNA from virus or apoptotic cells. HIF-1α played a fundamental role in this synergy. Moreover, overexpression of HIF-1α enhanced RASF-mediated inflammatory T cell expansion, inducing more proinflammatory IFN-γ and IL-17 production.

Conclusion:

Our findings suggest that hypoxia and HIF-1α may function collaboratively with TLR-engaged inflammatory response to excerbrate the pathogenesis of RA, and HIF-1α might serve as a therapeutic target for this disease.

Disclosure:

F. Hu,
None;

R. Mu,
None;

J. Zhu,
None;

W. Shao,
None;

L. Shi,
None;

P. L. Cohen,
None;

X. Qiu,
None;

Z. Li,
None.

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