Analysys of upregulated gene expression of interleukin-15 by synoviocytes in patients with rheumatoid arthritis

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TNFα-TNF receptor signaling is known to play a pivotal role in the promotion of joint destruction in Rheumatoid arthritis (RA). It has been recently reported that Interleukin-15 (IL-15) a newly discovered cytokine largely produced by macrophages, is increased in synovial fluid in RA, and can mediate secretion of TNFα. In current study, upregulated mRNA expression of IL-15 in rheumatoid synoviocytes was investigated by using freshly isolated and cultured synoviocytes from RA or osteoarthritis (OA) patients. mRNA expression analyzes using RT-PCR showed upregulated expression of IL-15 by synoviocytes, not only from RA patients but also from some OA patients. Expression of IL-15 was also observed in both RA and OA synoviocytes at protein levels by using intracellular FACS staining, indicating that IL-15 expression by itself is not specific to RA. When stimulated by TNFα or LPS, both RA and OA synoviocytes showed stimulation dependent upregulation of IL-15 mRNA. Since NF-κB and IRF-1 have been shown to be critical transcription factors in IL-15 mRNA regulation, EMSA analysis using these cis-acting elements from IL-15 promoters was also performed. Upon stimulation by either of TNFα or LPS, increased NF-κB DNA-binding activity was induced while not in IRF-1 DNA-binding. These results suggest that IL15 is not RA-specific inducer of TNFα expression, but enhancer of TNFα gene expression that mutually act through induction of NF-κB activities.