The suppressor of cytokine signaling–1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury
Hideo Yasukawa, … , Kenneth R. Chien, Kirk U. Knowlton
Hideo Yasukawa, … , Kenneth R. Chien, Kirk U. Knowlton
Published February 15, 2003
Citation Information: J Clin Invest. 2003;111(4):469-478. https://doi.org/10.1172/JCI16491.
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Article Cardiology

The suppressor of cytokine signaling–1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury

Abstract

Enteroviral infections of the heart are among the most commonly identified causes of acute myocarditis in children and adults and have been implicated in dilated cardiomyopathy. Although there is considerable information regarding the cellular immune response in myocarditis, little is known about innate signaling mechanisms within the infected cardiac myocyte that contribute to the host defense against viral infection. Here we show the essential role of Janus kinase (JAK) signaling in cardiac myocyte antiviral defense and a negative role of an intrinsic JAK inhibitor, the suppressor of cytokine signaling (SOCS), in the early disease process. Cardiac myocyte–specific transgenic expression of SOCS1 inhibited enterovirus-induced signaling of JAK and the signal transducers and activators of transcription (STAT), with accompanying increases in viral replication, cardiomyopathy, and mortality in coxsackievirus-infected mice. Furthermore, the inhibition of SOCS in the cardiac myocyte through adeno-associated virus–mediated (AAV-mediated) expression of a dominant-negative SOCS1 increased the myocyte resistance to the acute cardiac injury caused by enteroviral infection. These results indicate that strategies directed at inhibition of SOCS in the heart and perhaps other organs can augment the host-cell antiviral system, thus preventing viral-mediated end-organ damage during the early stages of infection.

Authors

Hideo Yasukawa, Toshitaka Yajima, Hervé Duplain, Mitsuo Iwatate, Masakuni Kido, Masahiko Hoshijima, Matthew D. Weitzman, Tomoyuki Nakamura, Sarah Woodard, Dingding Xiong, Akihiko Yoshimura, Kenneth R. Chien, Kirk U. Knowlton

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JAK-STAT antiviral defense in the cardiac myocyte and SOCS inhibition to...
JAK-STAT antiviral defense in the cardiac myocyte and SOCS inhibition to limit early virus-induced cardiac injury. (a) Virus infection of the heart stimulates cytokine-receptor signaling through the JAK-STAT pathway. Activation of the JAK-STAT pathway induces antiviral target gene transcription stimulating the innate viral defense in the cardiac myocyte. (b) While activation of the JAK-STAT pathway has an important role in antiviral defense, phosphorylated STAT also induces SOCS expression that attenuates the innate antiviral defense by inhibiting JAK signaling. As in SOCS1-transgenic mice, increased expression of SOCS in cardiac myocytes results in robust virus replication and cardiac injury. (c) The strategies aimed at inhibition of SOCS potentiate the innate antiviral actions of cytokines that utilize the JAK-STAT pathway, resulting in the prevention of virus-mediated myocardial injury. P, phosphorylated.