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Endogenous IL-15 Sustains Recruitment of IL-2R and Common and IL-2-Mediated Chemokine Production in Normal and Inflamed Human Gingival Fibroblasts¹

Akiko Ozawa^*,,, Hiroyuki Tada, Yumiko Sugawara, Akiko Uehara^*,, Takashi Sasano, Hidetoshi Shimauchi, Haruhiko Takada and Shunji Sugawara^2,*

^* Division of Oral Immunology, Division of Oral Microbiology, and Division of Periodontology and Endodontology, Department of Oral Biology, and Division of Oral Diagnosis, Department of Oral Medicine and Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan

We recently reported that anti-IL-15 neutralizing mAb has been shown to inhibit production of MCP-1 in response to IL-2 from normal human gingival fibroblasts (HGF), the major constituent of gingival tissue. In the present study, we examined the expression of IL-2R and IL-15R subunits in HGF from normal and inflamed regions and the role of endogenous IL-15 in IL-2-mediated signaling. Normal HGF expressed IL-2R and common -chain (_c) but not IL-2R or IL-15R, whereas inflamed HGF expressed IL-2R, IL-15R, IL-2R, and _c, as assessed by RT-PCR and flow cytometry. Exogenous IL-2 and IL-15 induced production of MCP-1 but not IL-8 in normal HGF, and induced the production of both chemokines in inflamed HGF. Both HGF constitutively transcribed the 48 aa-IL-15 isoform, and the isoform was not actively secreted but rather existed as a membrane-bound form. Pretreatment with anti-IL-15 neutralizing mAb for 24 h completely inhibited the production of MCP-1 induced by IL-2 and IL-15 and IL-2-induced phosphorylation of Jak 1 and 3 in HGF. The pretreatment and RNA interference targeted to IL-15 mRNA resulted in total inhibition of the IL-2R and _c expression at mRNA and protein levels. Furthermore, excess amounts of IL-2 restored the inhibitory effect of anti-IL-15, inhibition of NF-B abrogated the expression of IL-2R and _c, and IL-2-induced-nuclear translocation of NF-B was completely inhibited by the RNA interference in HGF. These results suggest that endogenous membrane-bound IL-15 sustains recruitment of IL-2R and _c through activation of NF-B in HGF.

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