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

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.

• Authors: Fanlei Hu, Rong Mu, Jiaxin Zhu, Lianjie Shi, Yingni Li, Xu Liu, Wenwei Shao, Guiye Li, Minghui Li, Yin Su, Philip L Cohen, Xiaoyan Qiu, Zhanguo Li
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 73 Issue 5 Pg. 928-36 (May 2014) ISSN: 1468-2060 [Electronic] England
• PMID: 23644550 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Toll-Like Receptors

Topics

• Arthritis, Rheumatoid (immunology, metabolism)
• Cell Hypoxia
• Cells, Cultured
• Enzyme-Linked Immunosorbent Assay
• Fibroblasts (metabolism)
• Flow Cytometry
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Immunity, Innate (immunology)
• Inflammation (immunology, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• Synovial Membrane (metabolism)
• Toll-Like Receptors (metabolism)