doi: 10.1161/hc5001.100629
(Circulation. 2001;104:3145.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Interleukin-12 Receptor/STAT4 Signaling Is Required for the Development of Autoimmune Myocarditis in Mice by an Interferon-
–Independent Pathway
From the Department of Pathology (M.A., Y.W., Z.K., E.A.S., K.M.D., A.A.S.A., N.R.R) and the W. Harry Feinstone Department of Molecular Microbiology and Immunology (M.A., N.R.R.) of The Johns Hopkins Medical Institutions, Baltimore, Md. Dr Sadighi Akha is now at the Department of Pathology, University of Michigan Medical School, Ann Arbor.
Correspondence to Noel R. Rose, MD, PhD, Department of Pathology, The Johns Hopkins University, Ross Building, Room 659, 720 Rutland Ave, Baltimore, MD 21205. E-mail nrrose{at}jhsph.edu
Background— Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses. This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-
.
Methods and Results— We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization. Both IL-12Rß1–deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN- is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN- suppresses EAM. Lack of IFN- due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-–deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2–producing cells; and heightened ability to produce cytokines on stimulation in vitro. Treatment of mice with recombinant IFN- suppressed the development of myocarditis.
Conclusions— IL-12/IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN- plays a protective role. The disease-limiting effects of IFN- might be explained by its ability to control the expansion of activated T lymphocytes.
Key Words: immunology • interleukins • myocarditis • myosin • inflammation
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