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

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

Research output: Contribution to journalArticle

88 Citations (Scopus)

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 endorgan damage during the early stages of infection.

Original languageEnglish
Pages (from-to)469-478
Number of pages10
JournalJournal of Clinical Investigation
Volume111
Issue number4
DOIs
Publication statusPublished - 2003 Feb
Externally publishedYes

Fingerprint

Enterovirus
Janus Kinases
Cardiac Myocytes
Cytokines
Wounds and Injuries
Myocarditis
Antiviral Agents
Infection
Therapeutics
Dependovirus
Dilated Cardiomyopathy
Virus Diseases
Transducers
Cardiomyopathies
Cellular Immunity
Muscle Cells
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yasukawa, H., Yajima, T., Duplain, H., Iwatate, M., Kido, M., Hoshijima, M., ... Knowlton, K. U. (2003). The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury. Journal of Clinical Investigation, 111(4), 469-478. https://doi.org/10.1172/JCI200316491

The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury. / Yasukawa, Hideo; Yajima, Toshitaka; Duplain, Hervé; Iwatate, Mitsuo; Kido, Masakuni; Hoshijima, Masahiko; Weitzman, Matthew D.; Nakamura, Tomoyuki; Woodard, Sarah; Xiong, Dingding; Yoshimura, Akihiko; Chien, Kenneth R.; Knowlton, Kirk U.

In: Journal of Clinical Investigation, Vol. 111, No. 4, 02.2003, p. 469-478.

Research output: Contribution to journalArticle

Yasukawa, H, Yajima, T, Duplain, H, Iwatate, M, Kido, M, Hoshijima, M, Weitzman, MD, Nakamura, T, Woodard, S, Xiong, D, Yoshimura, A, Chien, KR & Knowlton, KU 2003, 'The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury', Journal of Clinical Investigation, vol. 111, no. 4, pp. 469-478. https://doi.org/10.1172/JCI200316491
Yasukawa, Hideo ; Yajima, Toshitaka ; Duplain, Hervé ; Iwatate, Mitsuo ; Kido, Masakuni ; Hoshijima, Masahiko ; Weitzman, Matthew D. ; Nakamura, Tomoyuki ; Woodard, Sarah ; Xiong, Dingding ; Yoshimura, Akihiko ; Chien, Kenneth R. ; Knowlton, Kirk U. / The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 4. pp. 469-478.
@article{5ca67c8d0d8c451cbe75a1b1ffa46d08,
title = "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 endorgan damage during the early stages of infection.",
author = "Hideo Yasukawa and Toshitaka Yajima and Herv{\'e} Duplain and Mitsuo Iwatate and Masakuni Kido and Masahiko Hoshijima and Weitzman, {Matthew D.} and Tomoyuki Nakamura and Sarah Woodard and Dingding Xiong and Akihiko Yoshimura and Chien, {Kenneth R.} and Knowlton, {Kirk U.}",
year = "2003",
month = "2",
doi = "10.1172/JCI200316491",
language = "English",
volume = "111",
pages = "469--478",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

TY - JOUR

T1 - The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury

AU - Yasukawa, Hideo

AU - Yajima, Toshitaka

AU - Duplain, Hervé

AU - Iwatate, Mitsuo

AU - Kido, Masakuni

AU - Hoshijima, Masahiko

AU - Weitzman, Matthew D.

AU - Nakamura, Tomoyuki

AU - Woodard, Sarah

AU - Xiong, Dingding

AU - Yoshimura, Akihiko

AU - Chien, Kenneth R.

AU - Knowlton, Kirk U.

PY - 2003/2

Y1 - 2003/2

N2 - 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 endorgan damage during the early stages of infection.

AB - 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 endorgan damage during the early stages of infection.

UR - http://www.scopus.com/inward/record.url?scp=0037330278&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037330278&partnerID=8YFLogxK

U2 - 10.1172/JCI200316491

DO - 10.1172/JCI200316491

M3 - Article

C2 - 12588885

AN - SCOPUS:0037330278

VL - 111

SP - 469

EP - 478

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -