Lack of IL-6 during Coxsackievirus Infection Heightens the Early Immune Response Resulting in Increased Severity of Chronic Autoimmune Myocarditis

Abstract

BackgroundChronic myocarditis is often initiated by viral infection, the most common of which is coxsackievirus infection. The precise mechanism by which viral infection leads to chronic autoimmune pathology is poorly understood, however it is clear that the early immune response plays a critical role. Previous results have shown that the inflammatory cytokine interleukin (IL)-6 is integral to the development of experimental-induced autoimmune myocarditis. However, the function of IL-6 during viral-mediated autoimmunity has yet to be elucidated.Methods and ResultsTo address the requirement of IL-6 during disease induction, IL-6 deficient mice were infected with coxsackievirus B3 (CB3). Following infection, mice lacking IL-6 developed increased chronic autoimmune disease pathology compared to wild type controls without a corresponding change in the level of viral replication in the heart. This increase in disease severity was accompanied by elevated levels of TNF-α, MCP-1, IL-10, activated T cells and cardiac infiltrating macrophage/monocytes. Injection of recombinant IL-6 early following infection in the IL-6 deficient mice was sufficient to lower the serum cytokines TNF-α and IL-10 as well as the serum chemokines MCP-1, MIP-1β, RANTES and MIG with a corresponding decrease in the chronic disease pathology strongly suggests an important regulatory role for IL-6 during the early response.ConclusionsWhile IL-6 plays a pathogenic role in experimental-induced autoimmune disease, its function following viral-induced autoimmunity is not reprised. By regulating the early immune response and thereby controlling the severity of chronic disease, IL-6 directs the outcome of chronic autoimmune myocarditis.

Sustained High Levels of Interleukin-6 Contribute to the Pathogenesis of Enterovirus 71 in a Neonate Mouse Model

“…Our finding appears to contradict two recent studies which reported that IL-6-deficient mice infected with EV71 (26) or coxsackievirus B3 (37), a close relative to EV71 that belongs to the same genus, displayed increased disease severity compared to their immunocompetent counterparts, and administration of recombinant IL-6 early postinfection was sufficient to decrease the chronic disease pathology (37). These studies thus supported a protective role for IL-6 during EV71 infection.…”

Novel Nonmajor Histocompatibility Complex–Linked Loci From Mouse Chromosome 17 Confer Susceptibility to Viral-Mediated Chronic Autoimmune Myocarditis

“…These assays were performed as previously described. 19 Heart samples were collected at days 3 and 7 after CB3 infection.…”

The Key Players of Coxsackievirus-Induced Myocarditis

“…Work done by Poffenberger and colleagues has shown a significant increase in disease severity with the absence of IL-6 after coxsackievirus B3 infection in mice. An increase in inflammatory mediators associated with the progression of myocarditis such as TNF-and MCP1 was observed in concordance with the increase in disease severity (Poffenberger et al 2009). Without IL-6 to regulate the early immune response after infection, the early inflammatory response leads to increased chronic myocarditis severity as the disease progresses (Poffenberger et al 2009).…”

“…An increase in inflammatory mediators associated with the progression of myocarditis such as TNF-and MCP1 was observed in concordance with the increase in disease severity (Poffenberger et al 2009). Without IL-6 to regulate the early immune response after infection, the early inflammatory response leads to increased chronic myocarditis severity as the disease progresses (Poffenberger et al 2009). An important factor affecting the immune response to the virus and viral clearance is the pro-inflammatory cytokine interferon-(IFN ).…”

“…Our lab has also investigated the role of IL-6 in disease severity. Poffenberger et al demonstrated that in the absence of IL-6, a greater early immune response occurred, instigating a severe chronic disease pathology (Poffenberger et al 2009). Recently, Poffenberger et al described susceptibility loci on chromosome 17 that implicate the highly suggested genetic component as a factor dictating viral myocarditis pathogenesis (Poffenberger et al 2010).…”