Toll-like Receptor 4-induced Cytokine Production Circumvents Protection Conferred by TGF-beta in Coxsackievirus-Mediated Autoimmune Myocarditis

Clin Immunol. 2006 Dec;121(3):339-49. doi: 10.1016/j.clim.2006.07.009. Epub 2006 Sep 11.

Abstract

Coxsackie B virus (CBV) infections are a leading cause of autoimmune myocarditis associated with inflammatory heart disease and sudden death in young adults. Previously, we demonstrated that transgenic expression of the immunosuppressive cytokine, transforming growth factor-beta (TGF-beta), specifically in the pancreas protected otherwise susceptible mice from CBV-mediated autoimmune myocarditis. Herein, we demonstrate that macrophages from these transgenic mice fail to upregulate the costimulatory molecule CD40 following infection, suggesting that pancreatic TGF-beta protects by limiting antigen stimulation. We further demonstrate that co-administration of LPS from Salmonella minnesota, a Toll-like receptor (TLR)-4 ligand, with CBV infection overcomes protection whereas the TLR-2 agonist, LPS from Porphyromonas gingivalis, does not. Furthermore, LPS-mediated disease induction correlates with increased levels of pro-inflammatory cytokines. Interestingly, the action of LPS (TLR-4) did not alter antibody isotype switching, increase viral replication or modulate CD40 expression. Instead, LPS breaks protection through an alternative mechanism specific to TLR-4 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Autoantibodies / immunology
  • Autoimmune Diseases / etiology
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism*
  • Autoimmune Diseases / pathology
  • Cells, Cultured
  • Coxsackievirus Infections / complications
  • Coxsackievirus Infections / metabolism*
  • Coxsackievirus Infections / virology
  • Cytokines / biosynthesis*
  • Enterovirus / physiology*
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Myocarditis / etiology
  • Myocarditis / immunology
  • Myocarditis / metabolism*
  • Myocarditis / pathology
  • Pancreas / immunology
  • Pancreas / metabolism
  • Swine
  • Toll-Like Receptor 4 / agonists
  • Toll-Like Receptor 4 / metabolism*
  • Transforming Growth Factors / genetics
  • Transforming Growth Factors / metabolism*
  • Virus Replication

Substances

  • Autoantibodies
  • Cytokines
  • Lipopolysaccharides
  • Toll-Like Receptor 4
  • Transforming Growth Factors