Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling

Toshitaka Yajima, Hideo Yasukawa, Eun Seok Jeon, Dingding Xiong, Andrea Dorner, Mitsuo Iwatate, Miwako Nara, Hanbing Zhou, Daphne Summers-Torres, Masahiko Hoshijima, Kenneth R. Chien, Akihiko Yoshimura, Kirk U. Knowlton

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

BACKGROUND - Little is known about innate immune mechanisms within the cardiac myocyte that determine susceptibility to enterovirus infection, an important cause of myocarditis and subsequent heart failure. Although interferon (IFN) generally plays a key role in innate immunity, ablation of IFN receptors has little or no effect on acute coxsackievirus B3 infection in the heart. Interestingly, gp130-cytokine-mediated stimulation of neonatal ventricular myocytes has a cytoprotective effect against virus infection in culture that can be inhibited by suppressors of cytokine signaling (SOCS)-3, a physiological inhibitor of gp130 signaling that does not affect IFN signaling. Therefore, we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling. METHODS AND RESULTS - We generated cardiac-specific SOCS3 transgenic mice. Despite an intact IFN-mediated antiviral response in adult transgenic myocytes, there was a marked increase in susceptibility to viral infection in the SOCS3 transgenic mouse hearts. This indicated the presence of IFN-independent innate defense mechanisms within the cardiac myocyte. Subsequently, we demonstrated that cardiac-specific gp130-knockout mice also had increased susceptibility to viral infection. Furthermore, we demonstrated that the gp130-mediated increase in survival of infected myocytes occurred through a signal transducers and activators of transcription-3-dependent mechanism that did not affect viral replication. This was accompanied by a persistent expression of full-length dystrophin after coxsackievirus B3 infection. In addition, we found that both SOCS3 transgenic and gp130-deficient mice had a decrease in α-sarcoglycan. CONCLUSIONS - SOCS3-mediated regulation of gp130 signaling can affect susceptibility to viral infection in the heart. Increased cardiac cell survival through gp130-signal transducers and activators of transcription-3 signaling appears to play an important role in preserving nondividing cardiac myocytes until specific immune responses begin to clear the virus.

Original languageEnglish
Pages (from-to)2364-2373
Number of pages10
JournalCirculation
Volume114
Issue number22
DOIs
Publication statusPublished - 2006 Nov
Externally publishedYes

Fingerprint

Virus Diseases
Cardiac Myocytes
Interferons
Coxsackievirus Infections
Muscle Cells
STAT3 Transcription Factor
Transgenic Mice
Cytokine Receptor gp130
Sarcoglycans
Enterovirus Infections
Interferon Receptors
Cytokines
Dystrophin
Myocarditis
Innate Immunity
Knockout Mice
Antiviral Agents
Cell Survival
Heart Failure
Viruses

Keywords

  • Heart failure
  • Immune system
  • Infection
  • Molecular biology
  • Myocarditis
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Yajima, T., Yasukawa, H., Jeon, E. S., Xiong, D., Dorner, A., Iwatate, M., ... Knowlton, K. U. (2006). Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling. Circulation, 114(22), 2364-2373. https://doi.org/10.1161/CIRCULATIONAHA.106.642454

Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling. / Yajima, Toshitaka; Yasukawa, Hideo; Jeon, Eun Seok; Xiong, Dingding; Dorner, Andrea; Iwatate, Mitsuo; Nara, Miwako; Zhou, Hanbing; Summers-Torres, Daphne; Hoshijima, Masahiko; Chien, Kenneth R.; Yoshimura, Akihiko; Knowlton, Kirk U.

In: Circulation, Vol. 114, No. 22, 11.2006, p. 2364-2373.

Research output: Contribution to journalArticle

Yajima, T, Yasukawa, H, Jeon, ES, Xiong, D, Dorner, A, Iwatate, M, Nara, M, Zhou, H, Summers-Torres, D, Hoshijima, M, Chien, KR, Yoshimura, A & Knowlton, KU 2006, 'Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling', Circulation, vol. 114, no. 22, pp. 2364-2373. https://doi.org/10.1161/CIRCULATIONAHA.106.642454
Yajima, Toshitaka ; Yasukawa, Hideo ; Jeon, Eun Seok ; Xiong, Dingding ; Dorner, Andrea ; Iwatate, Mitsuo ; Nara, Miwako ; Zhou, Hanbing ; Summers-Torres, Daphne ; Hoshijima, Masahiko ; Chien, Kenneth R. ; Yoshimura, Akihiko ; Knowlton, Kirk U. / Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling. In: Circulation. 2006 ; Vol. 114, No. 22. pp. 2364-2373.
@article{0a27e0b027474969ad12d4f852c5ebb7,
title = "Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling",
abstract = "BACKGROUND - Little is known about innate immune mechanisms within the cardiac myocyte that determine susceptibility to enterovirus infection, an important cause of myocarditis and subsequent heart failure. Although interferon (IFN) generally plays a key role in innate immunity, ablation of IFN receptors has little or no effect on acute coxsackievirus B3 infection in the heart. Interestingly, gp130-cytokine-mediated stimulation of neonatal ventricular myocytes has a cytoprotective effect against virus infection in culture that can be inhibited by suppressors of cytokine signaling (SOCS)-3, a physiological inhibitor of gp130 signaling that does not affect IFN signaling. Therefore, we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling. METHODS AND RESULTS - We generated cardiac-specific SOCS3 transgenic mice. Despite an intact IFN-mediated antiviral response in adult transgenic myocytes, there was a marked increase in susceptibility to viral infection in the SOCS3 transgenic mouse hearts. This indicated the presence of IFN-independent innate defense mechanisms within the cardiac myocyte. Subsequently, we demonstrated that cardiac-specific gp130-knockout mice also had increased susceptibility to viral infection. Furthermore, we demonstrated that the gp130-mediated increase in survival of infected myocytes occurred through a signal transducers and activators of transcription-3-dependent mechanism that did not affect viral replication. This was accompanied by a persistent expression of full-length dystrophin after coxsackievirus B3 infection. In addition, we found that both SOCS3 transgenic and gp130-deficient mice had a decrease in α-sarcoglycan. CONCLUSIONS - SOCS3-mediated regulation of gp130 signaling can affect susceptibility to viral infection in the heart. Increased cardiac cell survival through gp130-signal transducers and activators of transcription-3 signaling appears to play an important role in preserving nondividing cardiac myocytes until specific immune responses begin to clear the virus.",
keywords = "Heart failure, Immune system, Infection, Molecular biology, Myocarditis, Signal transduction",
author = "Toshitaka Yajima and Hideo Yasukawa and Jeon, {Eun Seok} and Dingding Xiong and Andrea Dorner and Mitsuo Iwatate and Miwako Nara and Hanbing Zhou and Daphne Summers-Torres and Masahiko Hoshijima and Chien, {Kenneth R.} and Akihiko Yoshimura and Knowlton, {Kirk U.}",
year = "2006",
month = "11",
doi = "10.1161/CIRCULATIONAHA.106.642454",
language = "English",
volume = "114",
pages = "2364--2373",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "22",

}

TY - JOUR

T1 - Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling

AU - Yajima, Toshitaka

AU - Yasukawa, Hideo

AU - Jeon, Eun Seok

AU - Xiong, Dingding

AU - Dorner, Andrea

AU - Iwatate, Mitsuo

AU - Nara, Miwako

AU - Zhou, Hanbing

AU - Summers-Torres, Daphne

AU - Hoshijima, Masahiko

AU - Chien, Kenneth R.

AU - Yoshimura, Akihiko

AU - Knowlton, Kirk U.

PY - 2006/11

Y1 - 2006/11

N2 - BACKGROUND - Little is known about innate immune mechanisms within the cardiac myocyte that determine susceptibility to enterovirus infection, an important cause of myocarditis and subsequent heart failure. Although interferon (IFN) generally plays a key role in innate immunity, ablation of IFN receptors has little or no effect on acute coxsackievirus B3 infection in the heart. Interestingly, gp130-cytokine-mediated stimulation of neonatal ventricular myocytes has a cytoprotective effect against virus infection in culture that can be inhibited by suppressors of cytokine signaling (SOCS)-3, a physiological inhibitor of gp130 signaling that does not affect IFN signaling. Therefore, we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling. METHODS AND RESULTS - We generated cardiac-specific SOCS3 transgenic mice. Despite an intact IFN-mediated antiviral response in adult transgenic myocytes, there was a marked increase in susceptibility to viral infection in the SOCS3 transgenic mouse hearts. This indicated the presence of IFN-independent innate defense mechanisms within the cardiac myocyte. Subsequently, we demonstrated that cardiac-specific gp130-knockout mice also had increased susceptibility to viral infection. Furthermore, we demonstrated that the gp130-mediated increase in survival of infected myocytes occurred through a signal transducers and activators of transcription-3-dependent mechanism that did not affect viral replication. This was accompanied by a persistent expression of full-length dystrophin after coxsackievirus B3 infection. In addition, we found that both SOCS3 transgenic and gp130-deficient mice had a decrease in α-sarcoglycan. CONCLUSIONS - SOCS3-mediated regulation of gp130 signaling can affect susceptibility to viral infection in the heart. Increased cardiac cell survival through gp130-signal transducers and activators of transcription-3 signaling appears to play an important role in preserving nondividing cardiac myocytes until specific immune responses begin to clear the virus.

AB - BACKGROUND - Little is known about innate immune mechanisms within the cardiac myocyte that determine susceptibility to enterovirus infection, an important cause of myocarditis and subsequent heart failure. Although interferon (IFN) generally plays a key role in innate immunity, ablation of IFN receptors has little or no effect on acute coxsackievirus B3 infection in the heart. Interestingly, gp130-cytokine-mediated stimulation of neonatal ventricular myocytes has a cytoprotective effect against virus infection in culture that can be inhibited by suppressors of cytokine signaling (SOCS)-3, a physiological inhibitor of gp130 signaling that does not affect IFN signaling. Therefore, we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling. METHODS AND RESULTS - We generated cardiac-specific SOCS3 transgenic mice. Despite an intact IFN-mediated antiviral response in adult transgenic myocytes, there was a marked increase in susceptibility to viral infection in the SOCS3 transgenic mouse hearts. This indicated the presence of IFN-independent innate defense mechanisms within the cardiac myocyte. Subsequently, we demonstrated that cardiac-specific gp130-knockout mice also had increased susceptibility to viral infection. Furthermore, we demonstrated that the gp130-mediated increase in survival of infected myocytes occurred through a signal transducers and activators of transcription-3-dependent mechanism that did not affect viral replication. This was accompanied by a persistent expression of full-length dystrophin after coxsackievirus B3 infection. In addition, we found that both SOCS3 transgenic and gp130-deficient mice had a decrease in α-sarcoglycan. CONCLUSIONS - SOCS3-mediated regulation of gp130 signaling can affect susceptibility to viral infection in the heart. Increased cardiac cell survival through gp130-signal transducers and activators of transcription-3 signaling appears to play an important role in preserving nondividing cardiac myocytes until specific immune responses begin to clear the virus.

KW - Heart failure

KW - Immune system

KW - Infection

KW - Molecular biology

KW - Myocarditis

KW - Signal transduction

UR - http://www.scopus.com/inward/record.url?scp=33751555062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33751555062&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.106.642454

DO - 10.1161/CIRCULATIONAHA.106.642454

M3 - Article

VL - 114

SP - 2364

EP - 2373

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 22

ER -