title: Toll-like receptors expressed by synovial fibroblasts perpetuate Th1 and th17 cell responses in rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone and cartilage erosion. Synovial fibroblast- and T cell-mediated inflammation plays crucial roles in the pathogenesis of RA. However how this inflammation is initiated, propagated, and maintained remains controversial. Here, we systemically examined the contribution of toll-like receptors (TLRs) to the inflammatory mediator production as well as Th1 and Th17 cell hyperactivity in RA. Our results show that rheumatoid arthritis synovial fibroblasts (RASF) express a series of TLRs, including TLR2, TLR3, TLR4, and TLR9, with the predominant expression of TLR3. Moreover, the expression levels of these TLRs were higher than those in osteoarthritis synovial fibroblasts (OASF). Ligation of TLR3, as well as TLR2 and TLR4, resulted in vigorous production of inflammatory cytokines, matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) in RASF, with activation of the NF-κB, MAPK, and IRF3 pathways. More important, activation of these TLRs expressed by RASF exacerbated inflammatory Th1 and Th17 cell expansion both in cell-cell contact-dependent and inflammatory cytokine-dependent manners, which induced more IFN-γ and IL-17 accumulation. Targeting TLRs may modulate the inflammation in RA and provide new therapeutic strategies for overcoming this persistent disease.
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Fanlei
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Yingni
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Lianjie
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Huaqun
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Sumei
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Liling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D051193:Toll-Like Receptors