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 ␣-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.

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

“…Coxsackievirus usually infects cardiomyocytes and induces the expression of SOCS1 and SOCS3 in cardiomyocytes, which can result in evasion of immune responses and facilitation of virus replication by inhibition of JAK-STAT signaling (32,37). These findings indicate that it may be harmful to administer SOCS1 DNA in the acute phase of infectious myocarditis because it may augment viral replication by inhibition of IFN signaling.…”

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

“…For instance, the importance of the JAK2/STAT3 signaling axis for compensatory left ventricular remodeling is illustrated by the fact that pharmacological inhibition of JAK2 is sufficient to block the development of concentric hypertrophy during pressure overload [10]. Gp130-mediated STAT3 activation also seems to play a major role in preservation of cell survival during virally conditioned myocardial inflammation as both SOCS-3 transgenic mice and cardiac-specific gp130-knockout mice show an increase in susceptibility to viral infection of cardiomyocytes [165].…”

“…Gp130-mediated stimulation of cardiomyocytes has a cytoprotective effect against virus infection in culture that can be attenuated by SOCS3. Moreover, despite an intact IFN-mediated antiviral response transgenic mice with cardiomyocyte specific over-expression of SOCS3 display a marked increase in susceptibility to viral infection [165]. Similarly cardiomyocyte specific transgenic expression of SOCS1 inhibits enterovirus-induced signaling of JAK/STAT, with accompanying increase in viral replication, cardiomyopathy, and mortality in coxsackie virus-infected mice [170].…”

Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice

“…[21][22][23] The pBSII-aMHC-LOXL-1 vector was constructed by subcloning the human LOXL-1 cDNA (accession no: NM_005576) into the pBSII-aMHC plasmid (generously provided by S Morimoto, Kyushu University). After digestion with SalI, the fragment carrying the aMHC promoter and human LOXL-1 cDNA was microinjected into (C57BL/6 Â C3H) F1 (B6C3-F1) zygotes.…”

“…Mice were anesthetized with isoflurane and subjected to echocardiography as previously described. [22][23][24] Recording was performed as described previously. [22][23][24] …”