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Axis in the Development of Autoimmune Myocarditis: Induction by IL-12 and Protection by IFN-1
*
Medicine A, University Hospital, and
Basel Institute for Immunology, Basel, Switzerland;
Department of Pathology, University Hospital, Zurich, Switzerland;
Theodor Boveri Institut für Biowissenschaften, Wurzburg, Germany; and
¶ Department of Immunology, University of Cape Town, Cape Town, South Africa
IL-12 and IFN-
positively regulate each other and type 1
inflammatory responses, which are believed to cause tissue damage in
autoimmune diseases. We investigated the role of the IL-12/IFN-
(Th1) axis in the development of autoimmune myocarditis.
IL-12p40-deficient mice on a susceptible background resisted
myocarditis. In the absence of IL-12, autospecific CD4+ T
cells proliferated poorly and showed increased Th2 cytokine responses.
However, IFN--deficient mice developed fatal autoimmune disease, and
blockade of IL-4R signaling did not confer susceptibility to
myocarditis in IL-12p40-deficient mice, demonstrating that IL-12
triggers autoimmunity by a mechanism independent of the effector
cytokines IFN- and IL-4. In conclusion, our results suggest that the
IL-12/IFN- axis is a double-edged sword for the development of
autoimmune myocarditis. Although IL-12 mediates disease by
induction/expansion of Th1-type cells, IFN- production from these
cells limits disease progression.
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