title: Lipopolysaccharide increases the incidence of collagen-induced arthritis in mice through induction of protease HTRA-1 expression.
abstract: OBJECTIVE
  The protease HTRA-1 is closely associated with rheumatoid arthritis (RA). The molecular mechanisms that control HTRA-1 expression are currently unknown. This study was undertaken to determine the regulatory role of Toll-like receptors (TLRs) on HTRA-1 expression in mice with collagen-induced arthritis (CIA) and in synovial cells from RA patients.
  
  
  METHODS
  HTRA-1 messenger RNA and protein production in mouse fibroblasts, mouse macrophages, and freshly isolated RA patient synovial cells treated with TLR ligands were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Arthritis incidence and severity were determined using clinical scores and histopathologic analysis. Involvement of HTRA-1 in lipopolysaccharide (LPS)-increased arthritis incidence and severity in mice was determined using anti-HTRA-1 monoclonal antibody. The signal pathways involved in HTRA-1 expression were accessed by specific inhibitors, RNA interference, dual-luciferase reporter, and chromatin immunoprecipitation methods.
  
  
  RESULTS
  LPS and tenascin-C, but not the other TLR ligands tested, strongly induced HTRA-1 expression. LPS significantly increased HTRA-1 expression in the joint tissue as well as arthritis incidence and severity in mice with CIA. Blocking HTRA-1 by antibody significantly decreased LPS-promoted CIA severity. Inhibiting NF-κB significantly decreased LPS-induced HTRA-1 expression in mouse and human cells. Dual-luciferase reporter assay and ChIP analysis showed that p65 directly binds to HTRA-1 promoter (amino acid 347).
  
  
  CONCLUSIONS
  Our findings indicate that TLR-4 activation increases HTRA-1 expression through the NF-κB pathway in fibroblasts and macrophages. HTRA-1 expression is involved in the enhancing effects of LPS on CIA. This study offers new insights into the regulation of HTRA-1 expression via LPS/TLR-4 and the role of HTRA-1 in RA pathogenesis.
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, and Chinese Academy of Sciences, Beijing, China.
authors: Yuzhu
authors: Y
authors: Hou
authors: Haijiang
authors: H
authors: Lin
authors: Linnan
authors: L
authors: Zhu
authors: Zhaoting
authors: Z
authors: Liu
authors: Fanlei
authors: F
authors: Hu
authors: Jianfeng
authors: J
authors: Shi
authors: Tao
authors: T
authors: Yang
authors: Xiaoyun
authors: X
authors: Shi
authors: Mingzhao
authors: M
authors: Zhu
authors: Bernard F
authors: BF
authors: Godley
authors: Qiang
authors: Q
authors: Wang
authors: Zhanguo
authors: Z
authors: Li
authors: Yong
authors: Y
authors: Zhao
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D015994:Incidence; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D013583:Synovial Membrane / Q000166:cytology / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000074289:High-Temperature Requirement A Serine Peptidase 1; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases