Tumor necrosis factor-alpha promotes myocarditis in female mice infected with coxsackievirus B3 through upregulation of CD1d on hematopoietic cells.
Coxsackievirus B3 (CVB3) induces cardiac inflammation (myocarditis) in male but not female C57BL/6 mice. Protection of females correlates with reduced expression of TNF-alpha and IL-1beta at both the mRNA and protein levels in the heart. Treatment of females with 300 ng/mouse of recombinant TNF-alpha on days +1 and +3 relative to infection restores myocarditis susceptibility to levels approximating those of infected male mice, showing that TNF-alpha deficiency is central to disease resistance. Female mice express little CD1d on spleen lymphocytes or cardiac myocytes, while females treated with TNF-alpha show increased CD1d expression in both cell populations. TNF-alpha treatment of male or female CD1d knockout (CD1dKO) mice failed to restore myocarditis susceptibility, demonstrating that of the multiple potential TNF-alpha activities, its ability to upregulate this non-classical major histocompatibility complex antigen is its dominant function in myocarditis susceptibility. Bone marrow chimeric mice were produced between female C57BL/6 and C57BL/6 CD1dKO mice so that either hematopoietic or non-hematopoietic cells were CD1d deficient. TNF-alpha treatment of chimeric mice having wild-type (CD1d+) hematopoietic cells restored myocarditis susceptibility, while TNF-alpha treatment of chimeric mice having CD1dKO hematopoietic cells, but CD1d+ myocytes, failed to develop myocarditis, showing that CD1d expression in lymphoid cells controls disease susceptibility.
Huber
Sally
S
Department of Pathology, University of Vermont, Colchester, Vermont 05446, USA. sally.huber@uvm.edu
D000818:Animals; D055610:Antigens, CD1d / Q000096:biosynthesis* / Q000235:genetics; D003384:Coxsackievirus Infections / Q000276:immunology / Q000473:pathology*; D004198:Disease Susceptibility; D029822:Enterovirus B, Human / Q000276:immunology*; D005260:Female; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D015854:Up-Regulation
D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D014409:Tumor Necrosis Factor-alpha