Sugiura T, Harigai M, Kawaguchi Y, Takagi K, Fukasawa C, Ohsako-Higami S, Ohta S, Tanaka M, Hara M, Kamatani N. Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan.

In polymyositis (PM)/dermatomyositis (DM), various cytokines, especially macrophage-derived cytokines such as IL-1alpha, IL-1beta and tumor necrosis factor (TNF)-alpha, are expressed in the inflammatory foci. We previously reported that IL-15, a novel cytokine with a biological activity similar to that of IL-2, is expressed in muscle cells in PM/DM.

In the present study, we set out to investigate the regulation of IL-15 in cultured myoblasts. Myoblasts constitutively produced a low level of IL-15 and the production was augmented by stimulation with IFN-gamma, IL-1alpha, IL-1beta, TNF-alpha or lipopolysaccharide (LPS) in a dose-dependent manner. These stimuli also enhanced the expression of IL-15 mRNA. About 30-40% of IL-15 was detected intracellularly, while the rest was released into the culture supernatant.

Immunohistochemical staining revealed that intracellular IL-15 was localized in the perinuclear area of the cytoplasm in the myoblasts.

Despite the considerable amounts of intracellular IL-15, the myoblasts predominantly expressed authentic IL-15 mRNA isoform. This isoform generates IL-15 with long signal peptide preprotein, which is all to be secreted. The biological activity of IL-15 secreted from the myoblasts was examined using an IL-15-dependent murine T cell line, CTLL-2.

Culture supernatants of the myoblasts induced a proliferative response of CTLL-2 and this was specifically inhibited by anti-IL-15 antibody.

These results suggest that inflammatory stimuli induce the production of IL-15 in the muscle cells in PM/DM, and IL-15 may contribute to the immunopathogenesis by augmenting recruitment and activation of the infiltrating T cells. Blocking of IL-15 production might be of therapeutic value in PM/DM.

PMID: 12147628 [PubMed - in process]