Interleukin-17A promotes rheumatoid arthritis synoviocytes migration and invasion under hypoxia by increasing MMP2 and MMP9 expression through NF-κB/HIF-1α pathway

• Published in: Molecular immunology 2013-03, Vol.53 (3), p.227-236
• Main Authors: Li, Guoqing, Zhang, Yu, Qian, Yayun, Zhang, Hua, Guo, Shiyu, Sunagawa, Masataka, Hisamitsu, Tadashi, Liu, Yanqing
• Format: Article
• Language: English
• Subjects: Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Base Sequence; Cell Hypoxia - immunology; Cell Movement - drug effects; Cell Movement - immunology; Cells, Cultured; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - immunology; Gene Knockdown Techniques; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Interleukin-17 - metabolism; Interleukin-17 - pharmacology; Interleukin-17A; Invasion; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; Recombinant Proteins - pharmacology; Rheumatoid arthritis; RNA, Small Interfering - genetics; Signal Transduction; Synovial Membrane - drug effects; Synovial Membrane - immunology; Synovial Membrane - metabolism; Synovial Membrane - pathology; Synoviocytes
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2012.08.018

► IL-17A promoted RA-FLSs migration and invasion under hypoxia. ► Combined IL-17A with hypoxia contributed to RA-FLSs migration and invasiveness through upregulation of MMP2 and MMP9. ► IL-17A heightened HIF-1α and NF-κB activities in RA-FLSs under hypoxia. ► IL-17A upregulated MMP2 and MMP9 expression through activating an NF-κB/HIF-1α pathway under hypoxia. Both hypoxia and interleukin-17A (IL-17A) promote the migration and invasion of fibroblast-like synoviocytes (FLSs), which are critical for the pathogenesis of rheumatoid arthritis (RA). However, the biochemical pathways regulating IL-17A combined with hypoxia are not well defined. In this study, we found that co-stimulating RA-FLSs with IL-17A and hypoxia did not appear to promote the epithelial–mesenchymal transition (EMT), but did increase cell motility. We further showed that a proinvasive effect of IL-17A on FLSs under hypoxia might be through upregulation of matrix metalloproteinase 2 (MMP2) and MMP9. Moreover, IL-17A-induced expression of MMP2 and MMP9 under hypoxia was accompanied by increased activation of nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α). Knockdown or inhibition of HIF-1α and NF-κB by small interfering RNA or specific small molecule inhibitors blocked IL-17A-mediated and hypoxia-mediated MMP2 and MMP9 expression, cell migration, and invasion. In addition, the inhibition of NF-κB led to a marked decrease in the expression of HIF-1α, which indicated that IL-17A activated HIF-1α via the NF-κB pathway in hypoxia. Taken together, our observations suggest a synergetic effect of IL-17A and hypoxia that might contribute to the migration and invasion of RA-FLSs by upregulating the expression of MMP2 and MMP9 by activation of the NF-κB/HIF-1α pathway.