title: Hypoxia-inducible factor-1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis.
abstract: Synovial fibroblast hyperplasia, T-cell hyperactivity, B-cell overactivation, and the self-perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA). The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia-inducible factor-1α (HIF-1α) in RA synovial fibroblasts (RASFs). It remains unknown whether HIF-1α regulates interactions between RASFs and T cells and B cells. We report here that HIF-1α promotes the expression of inflammatory cytokines IL-6, IL-8, TNF-α, and IL-1β, and cell-cell contact mediators IL-15, vascular cell adhesion molecule (VCAM)-1, thrombospondin (TSP)-1, and stromal cell-derived factor (SDF)-1 in RASFs. Furthermore, HIF-1α perpetuates RASF-mediated inflammatory Th1- and Th17-cell expansion while differentially inhibiting regulatory B10 and innate-like B cells, leading to increased IFN-γ, IL-17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF-1α perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF-1α may provide new therapeutic strategies for overcoming this persistent disease.
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Fanlei
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Liling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Yingni
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Lianjie
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Immunology, School of Basic Medical Science, Peking University, Beijing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology* / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019409:Interleukin-15 / Q000235:genetics; D020381:Interleukin-17 / Q000276:immunology / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D013583:Synovial Membrane / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*; D019700:Thrombospondin 1 / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D001323:Autoantibodies; D054377:Chemokine CXCL12; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019409:Interleukin-15; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D019700:Thrombospondin 1; D019010:Vascular Cell Adhesion Molecule-1
keywords: B cell; Hypoxia-inducible factor-1α; Rheumatoid arthritis; Synovial fibroblast; T cell