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.
  
  
  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 alpha-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.
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0613, USA.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yajima
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Jeon
authors.forename: Dingding
authors.initials: D
authors.lastname: Xiong
authors.forename: Andrea
authors.initials: A
authors.lastname: Dorner
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iwatate
authors.forename: Miwako
authors.initials: M
authors.lastname: Nara
authors.forename: Hanbing
authors.initials: H
authors.lastname: Zhou
authors.forename: Daphne
authors.initials: D
authors.lastname: Summers-Torres
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Kirk U
authors.initials: KU
authors.lastname: Knowlton
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000453:epidemiology; D050822:Cytokine Receptor gp130 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004198:Disease Susceptibility; D004452:Echocardiography; D006321:Heart / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000502:physiology* / Q000821:virology*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000502:physiology; D014777:Virus Diseases / Q000235:genetics / Q000517:prevention & control*
chemical_list: C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130