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Ann Rheum Dis doi:10.1136/annrheumdis-2012-202444
  • Basic and translational research
  • Extended Report

Hypoxia and hypoxia-inducible factor-1α provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis

  1. Zhanguo Li1
  1. 1Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
  2. 2Department of Immunology, School of Basic Medical Science, Peking University, Beijing, China
  3. 3Department of Medicine, Temple University, Philadelphia, Pennsylvania, USA
  1. Correspondence to Professor Zhanguo Li, Department of Rheumatology and Immunology, Peking University People's Hospital, 11 Xizhimen South Street, Beijing 100044, China; zgli{at}yahoo.cn or Professor Xiaoyan Qiu, Department of Immunology, School of Basic Medical Science, Peking University, 38 Xueyuan Road, Beijing 100191, China; qiuxy{at}bjmu.edu.cn or Professor Philip L Cohen, Department of Medicine, Temple University, 3322 North Broad Street, Room 201, Philadelphia, PA 19140, USA; philco{at}temple.edu
  • Accepted 14 April 2013
  • Published Online First 3 May 2013

Abstract

Objectives Hyperplasia of synovial fibroblasts, infiltration with lymphocytes and tissue hypoxia are major characteristics of rheumatoid arthritis (RA). Extensive data support a key role for toll-like receptors (TLRs) in RA. Little is known regarding the impact of hypoxia on TLR-induced inflammation in RA. The aim of this study was to reveal the effects of hypoxia and its regulator, hypoxia-inducible factor-1α (HIF-1α), on the inflammatory response of RA synovial fibroblasts (RASF) to TLR ligands.

Methods Hypoxia was induced in RASF by incubation with Na2S2O4. TLR3 ligand polyIC, TLR2 ligand peptidoglycan, TLR4 ligand LPS and TLR9 ligand CpG were used to stimulate the cells. Effects of hypoxia on TLR-induced inflammatory mediators were determined by RT-PCR, qPCR and ELISA. Overexpression of HIF-1α as well as knocking-down its expression was used to reveal its fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry analysis of T helper (Th)1/Th17 cells, and IFN-γ/IL-17 production by ELISA after RASF/T cell coculture.

Results Hypoxia potentiated the expression of inflammatory cytokines, metalloproteinases and VEGF in RASF stimulated by different TLR ligands, especially polyIC, a synthetic mimic of dsRNA from viruses or apoptotic cells. HIF-1α played a fundamental role in this synergy. Moreover, HIF-1α overexpression enhanced RASF-mediated expansion of inflammatory Th1 and Th17 cells, leading to proinflammatory IFN-γ and IL-17 production.

Conclusions Our findings suggest that hypoxia and HIF-1α may function in conjunction with TLR-stimulated innate immune responses to drive inflammation in RA. This pathway may serve as a therapeutic target for the disease.

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