Expressional Patterns of Cytokines in a Murine Model of Acute Myocarditis: Early Expression of Cardiotrophin-1

Abstract

SUMMARY:To determine the role of cytokines in acute myocarditis, we examined expressional patterns of cardiotrophin-1 (CT-1), TNF-␣, and IL-1␣ in a murine model of acute myocarditis. Ten-day-old Institute of Cancer Research mice were injected with Coxsackievirus B3 and killed on Days 1, 2, 3, 4, 5, 7, 10, 14, and 28 of injection. TNF-␣ and IL-1␣ expressions were investigated on histological sections from each heart, and mRNA expression of TNF-␣, IL-1␣, and CT-1 in the heart was examined by reverse transcription-polymerase chain reaction and RNase protection assay. To determine myocardial regeneration, cardiomyocytic DNA synthesis was investigated using bromodeoxyuridine on Days 3, 5, 7, and 10, and the labeling index was calculated in each heart. Age-matched uninfected mice were used as controls. TNF␣ and IL-1␣ expression was first detected in the cardiomyocytes on Day 3 and reached the maximum level on Day 7, when inflammatory changes were most prominent. Although an increased expression of TNF␣ and IL-1␣ mRNA was also detected on Day 3, CT-1 mRNA expression was distinctly augmented on Day 2. The labeling indices in the hearts with myocarditis were significantly higher than in those of the controls in all of the time points examined. CT-1 expression preceded TNF-␣ and IL-1␣ expressions and active DNA synthesis in a murine model of acute myocarditis. All CVB3-infected mice with anti-glycoprotein-130 antibody treatment died within 6 days. CT-1 may exert a protective role by modulating cytokine production and by inducing cardiomyocytic proliferation in CVB3-infected murine hearts. (Lab Invest 2000, 80:433-440).V iral myocarditis results from a viral infection that induces myocardial necrosis and triggers a series of immune responses to eliminate the viral agent. Although several studies have examined the crucial roles of cytokines and the induction of apoptosis in the myocardium, the pathogenic mechanisms of myocarditis remain unclear

Coxsackievirus B3 activates nuclear factor kappa B transcription factor via a phosphatidylinositol-3 kinase/protein kinase B-dependent pathway to improve host cell viability

“…Tumour necrosis factor‐α is a strong activator of NFκB and its expression has been shown to increase in CVB3 myocarditis (Seko et al ., 1997; Freeman et al ., 1998; Okuno et al ., 2000). To determine the potential role of TNF‐α in NFκB activation, HeLa cells were treated with TNF‐α at the time of virus infection.…”

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

“…Since JAK-STAT activation occurs before there is significant infiltration with mononuclear lymphocytes, it appears to have a key role in the control of viral replication at the early stages of viral infection (Figure 7a). Viral infection induces expression of cytokines that activate JAK signaling -such as IFN-α/β, IFN-γ, gp130-related cytokines (CT-1, IL-6), IL-10, and IL-12 -at the early stages of myocarditis (35)(36)(37)(38)(39). The exogenous administration of these cytokines has been shown to ameliorate the severity of viral myocarditis in mice.…”

CXCL10 Inhibits Viral Replication Through Recruitment of Natural Killer Cells in Coxsackievirus B3-Induced Myocarditis

“…Several cytokines and chemokines such as TNF-␣, IL-1␣, and MCP-1 are known to be produced in cardiomyocytes after CVB3 infection. 22,23 However, whether cardiomyocytes are capable to express CXCL10 is unknown. Here we showed for the first time that CXCL10 can be induced by IFN-␥ but not by CVB3 in primary adult mouse cardiomyocytes.…”