Journal
MOLECULAR IMMUNOLOGY
Volume 53, Issue 3, Pages 227-236Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2012.08.018
Keywords
Interleukin-17A; Invasion; Hypoxia; Synoviocytes; Matrix metalloproteinase; Rheumatoid arthritis
Categories
Funding
- National Natural Science Foundation of China [81173603]
- Postgraduate Research and Innovation Project of Jiangsu Province [CXZZ11-0998]
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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-kappa B (NF-kappa B)/hypoxia-inducible factor-1 alpha (HIF-1 alpha). Knockdown or inhibition of HIF-1 alpha and NF-kappa B 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-kappa B led to a marked decrease in the expression of HIF-1 alpha, which indicated that IL-17A activated HIF-1 alpha via the NF-kappa B 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-kappa B/HIF-1 alpha pathway. (c) 2012 Elsevier Ltd. All rights reserved.
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