Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-γ-independent pathway

Marina Afanasyeva, Yan Wang, Ziya Kaya, Elizabeth A. Stafford, K. Malte Dohmen, Amir A. Sadighi Akha, Noel R. Rose

Research output: Contribution to journalArticle

Abstract

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)-γ. 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-12Rβ1-deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN-γ is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN-γ suppresses EAM. Lack of IFN-γ due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-γ-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-γ suppressed the development of myocarditis. Conclusions - IL-12/IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN-γ plays a protective role. The disease-limiting effects of IFN-γ might be explained by its ability to control the expansion of activated T lymphocytes.

Original languageEnglish (US)
Pages (from-to)3145-3151
Number of pages7
JournalCirculation
Volume104
Issue number25
DOIs
StatePublished - Dec 18 2001

Keywords

  • Immunology
  • Inflammation
  • Interleukins
  • Myocarditis
  • Myosin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Afanasyeva, M., Wang, Y., Kaya, Z., Stafford, E. A., Dohmen, K. M., Sadighi Akha, A. A., & Rose, N. R. (2001). Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-γ-independent pathway. Circulation, 104(25), 3145-3151. https://doi.org/10.1161/hc5001.100629