Increased IL-15 production of muscle cells in polymyositis and dermatomyositis.
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.
Sugiura
Tomoko
T
Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan. tsugiura@ior.twmu.ac.jp
Harigai
Masayoshi
M
Kawaguchi
Yasushi
Y
Takagi
Kae
K
Fukasawa
Chikako
C
Ohsako-Higami
Satomi
S
Ohta
Shuji
S
Tanaka
Michi
M
Hara
Masako
M
Kamatani
Naoyuki
N
D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D003882:Dermatomyositis / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D019409:Interleukin-15 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000276:immunology*; D017285:Polymyositis / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D019409:Interleukin-15; D008070:Lipopolysaccharides; D012333:RNA, Messenger