Recombinant Murine Interleukin-12 Facilitates Induction of Cardiac Myosin–Specific Type 1 Helper T Cells in Rats

From the Department of Immunology (Y.O., K.T., S.H., H.W., T.A.) and the First Department of Internal Medicine (Y.O., H.H., M.K., Y.A.), Niigata University School of Medicine, Niigata, Japan; the Department of Internal Medicine (T.I.), Kitasato University School of Medicine, Sagamihara, Japan; and the Division of Basic Traumatology, National Defense Medical College Research Institute (S.S.), Tokorozawa, Japan.

Correspondence to Yuji Okura, MD, First Department of Internal Medicine, Niigata University School of Medicine, Asahimachi, Niigata 951, Japan. E-mail dogwood{at}med.niigata-u.ac.jp

Abstract—Autoimmunity after viral myocarditis is considered to be one of the causes of dilated cardiomyopathy. Cytokines are assumed to play an important role in the pathogenesis. We recently reported that interleukin (IL)-2 and interferon (IFN)- mRNA are expressed in the myocardium of rats with experimental autoimmune myocarditis (EAM). However, the role of cytokines in autoimmune myocardial injury in detail is still not clear. Reverse transcription–polymerase chain reaction identified IL-12 (p40) mRNA in antigen-presenting cells in the initial phase of EAM. Cardiac myosin–specific T lymphocytes (MSTLs) were cultured with cardiac myosin peptide (CMP) in the presence of IL-2 and/or IL-12 and were transferred to other naive rats. The results showed that EAM could be effectively induced by transfer of MSTLs cultured with IL-12, whereas transfer of MSTLs cultured with IL-2 was less effective. However, IL-2 acts synergistically with IL-12, and MSTLs cultured with both cytokines most efficiently induce EAM. In vitro experiments showed that MSTLs cultured with both IL-12 and IL-2 produced a much greater amount of IFN- than did MSTLs cultured with either IL-12 or IL-2 alone. The amount of IFN- production was correlated with pathogenicity of MSTLs. Transfer experiments after sorting further demonstrated that the transfer was affected by CD4⁺ helper T (Th) cells but not by CD8⁺ cytotoxic T lymphocytes. IL-12 and IL-2 synergistically enhance the pathogenicity of MSTLs. Furthermore, a type 1 Th (Th1) cytokine, IFN-, which is a potent regulatory cytokine of autoimmunity, is produced by MSTLs. IL-12 and IL-2 potentiate the expansion of cardiac myosin–specific Th1 cells and play an important role in the development of autoimmune myocardial injury.

Key Words: helper T cell • cytokine • interleukin • autoimmunity • myocardial injury

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