Toll-like receptor 4-induced cytokine production circumvents protection conferred by TGF-beta in coxsackievirus-mediated autoimmune myocarditis.
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.
Richer
Martin J
MJ
Microbiology and Immunology, The University of British Columbia, 3551-2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.
Fang
Dianne
D
Shanina
Iryna
I
Horwitz
Marc S
MS
D000818:Animals; D030801:Animals, Genetically Modified; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000150:complications / Q000378:metabolism* / Q000821:virology; D016207:Cytokines / Q000096:biosynthesis*; D004770:Enterovirus / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009205:Myocarditis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D013552:Swine; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*; D015291:Transforming Growth Factors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D001323:Autoantibodies; D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D015291:Transforming Growth Factors