PIM-1 kinase is a novel regulator of proinflammatory cytokine-mediated responses in rheumatoid arthritis fibroblast-like synoviocytes. (10th September 2018)

• Record Type: Journal Article
• Authors: Ha, You-Jung; Choi, Yong Seok; Han, Dong Woo; Kang, Eun Ha; Yoo, In Seol; Kim, Jin Hyun; Kang, Seong Wook; Lee, Eun Young; Song, Yeong Wook; Lee, Yun Jong
• Is Part Of: Rheumatology. Volume 58:Number 1(2019)
• Page Start: 154
• Page End: 164
• Publication Date: 2018-09-10
• Subjects: RA -- fibroblast-like synoviocytes -- synovium -- PIM kinase; Rheumatism -- Periodicals; Rheumatology -- Periodicals; 616.723005
• DOI: 10.1093/rheumatology/key261
• Languages: English
• ISSNs: 1462-0324

Abstract

Abstract: Objectives: This study investigated the expression of proviral-integration site for Moloney murine leukaemia virus (PIM) -1 kinase in RA synovium and RA fibroblast-like synoviocytes (FLSs) along with its impact on RA-FLS aggressiveness. Methods: The expression of PIM kinases was assessed in synovial tissues by immunohistochemistry and double IF. After PIM-1 inhibition using either small-interfering RNA or the chemical inhibitor AZD1208, we performed proliferation and migration assays and measured the levels of MMPs and IL-6 released from RA-FLSs under stimulation with proinflammatory cytokines (TNF-α, S100A4 and IL-6/soluble IL-6 receptor). Additionally, PIM-1-associated downstream signalling pathways were analysed by immunoblotting. Results: Three isoforms of PIM kinases were immunodetected in the synovial tissues from patients with RA or OA. Specifically, PIM-1 and PIM-3 were upregulated in RA synovium and PIM-1 was expressed in T cells, macrophages and FLSs. Additionally, upon stimulation of RA-FLSs with TNF-α, S100A4 and IL-6/sIL-6R, PIM-1 and PIM-3, but not PIM-2, were significantly inducible. Moreover, PIM-1 knockdown or AZD1208 treatment significantly suppressed basal or cytokine-induced proliferation and migration of RA-FLS and the secretion of MMPs from stimulated RA-FLSs. PIM-1 knockdown significantly affected the phosphorylation levels of extracellular signal-regulated kinase and cAMP responsive element binding protein in RA-FLSs. Conclusion: PIM-1 was upregulated in RA synovial tissues and RA-FLSs and its inhibition significantly reduced the proliferation, migration and MMP production of RA-FLSs in vitro . These findings suggest PIM-1 as a novel regulator of the aggressive and invasive behaviour of RA-FLSs and indicate its potential as a target for RA treatment.