Stat3 is a pleiotropic transcription factor displaying different functions in distinct tissues under both physiological and pathological conditions. Recently, Stat3 was shown to be required for the differentiation of IL-17 secreting cells (Th17) from naïve CD4+ T cells. IL-17 production has been correlated with harmful inflammatory effects in auto-immune disorders both in human and mouse, because of its ability to trigger tissue damage. Accordingly IL-6, responsible for driving Th17 cells differentiation and known to act mainly through Stat3, is required for the development of several autoimmune diseases including rheumatoid arthritis, experimental auto-immune encephalomyelitis and auto-immune myocarditis. These observations imply Stat3 in the development and regulation of autoimmune diseases, but no model investigating Stat3 pathogenic functions in autoimmunity was so far available. We have recently generated knock/in mice expressing physiological levels of the constitutively active mutant form Stat3C under the control of its own promoter (Stat3C/C mice). These mice develop a lethal form of autoimmune myocarditis, characterized by abundant myeloid infiltration of the heart, production of anti-alpha myosin autoantibodies and high mRNA levels for proinflammatory cytokines, including IL-17, TNFa and IL-6, in the heart. Preliminary results suggest that Stat3C expression triggers myocarditis development acting both at the level of the hematopoietic cells and of the heart. In addition, the development of Th17 cells appears to be enhanced by Stat3C expression and Stat3C/C mice display enhanced circulating levels of the complement component C3, which is known to play an important role in auto-immune myocarditis. Thus, Stat3C/C mice appear to be a suitable model to study the role of chronically activated Stat3 in the development of autoimmunity, where it can apparently act at the level of both acquired and naïve immunity. Further characterization of this model may lead to identify potential new strategies for therapeutic intervention in auto-immune diseases.
Constitutively active Stat3 triggers the development of autoimmune myocarditis
CAMPOREALE, ANNALISA;MARINO, Francesca;BRERO, Alessia;CHIARLE, Roberto;LEVI, Renzo;POLI, Valeria
2009-01-01
Abstract
Stat3 is a pleiotropic transcription factor displaying different functions in distinct tissues under both physiological and pathological conditions. Recently, Stat3 was shown to be required for the differentiation of IL-17 secreting cells (Th17) from naïve CD4+ T cells. IL-17 production has been correlated with harmful inflammatory effects in auto-immune disorders both in human and mouse, because of its ability to trigger tissue damage. Accordingly IL-6, responsible for driving Th17 cells differentiation and known to act mainly through Stat3, is required for the development of several autoimmune diseases including rheumatoid arthritis, experimental auto-immune encephalomyelitis and auto-immune myocarditis. These observations imply Stat3 in the development and regulation of autoimmune diseases, but no model investigating Stat3 pathogenic functions in autoimmunity was so far available. We have recently generated knock/in mice expressing physiological levels of the constitutively active mutant form Stat3C under the control of its own promoter (Stat3C/C mice). These mice develop a lethal form of autoimmune myocarditis, characterized by abundant myeloid infiltration of the heart, production of anti-alpha myosin autoantibodies and high mRNA levels for proinflammatory cytokines, including IL-17, TNFa and IL-6, in the heart. Preliminary results suggest that Stat3C expression triggers myocarditis development acting both at the level of the hematopoietic cells and of the heart. In addition, the development of Th17 cells appears to be enhanced by Stat3C expression and Stat3C/C mice display enhanced circulating levels of the complement component C3, which is known to play an important role in auto-immune myocarditis. Thus, Stat3C/C mice appear to be a suitable model to study the role of chronically activated Stat3 in the development of autoimmunity, where it can apparently act at the level of both acquired and naïve immunity. Further characterization of this model may lead to identify potential new strategies for therapeutic intervention in auto-immune diseases.
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