Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart.
Inflammatory fibrosis is a characteristic feature of myocarditis, dilated cardiomyopathy (DCM), and congestive heart failure. Th1-type immune responses, mediated by interleukin (IL)-12-induced interferon (IFN)-gamma, are believed to exacerbate autoimmune diseases including myocarditis. In this study, we examined the effect of IL-12R beta 1 and IFN-gamma deficiency on the development of chronic CB3-induced myocarditis using knockout mice. We found increased chronic CB3-induced myocarditis (14.1 to 43.1%, P < 0.001); pericarditis (1.5 to 7.6%, P < 0.001); fibrosis (9.7 to 27.4%, P < 0.05); and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the hearts of IFN-gamma-deficient mice. All mice infected with CB3 developed DCM, but IFN-gamma-deficient mice developed a fibrous, adhesive pericarditis associated with increased numbers of degranulating mast cells (MCs) in the pericardium (26.6 to 45.9%, P < 0.01), increased histamine levels (716 to 1930 ng/g of heart, P < 0.01), and reduced survival (100 to 43%). In contrast, IL-12R beta 1 deficiency did not significantly alter the development of chronic myocarditis. Thus, IFN-gamma protects against the development of severe chronic myocarditis, pericarditis, and DCM after CB3 infection by reducing MC degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the heart.
Fairweather
DeLisa
D
Department of Pathology, Johns Hopkins Medical Institutions, 720 Rutland Ave., Baltimore, MD 21205, USA.
Frisancho-Kiss
Sylvia
S
Yusung
Susy A
SA
Barrett
Masheka A
MA
Davis
Sarah E
SE
Gatewood
Shannon J L
SJ
Njoku
Dolores B
DB
Rose
Noel R
NR
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D015550:Cell Degranulation; D002908:Chronic Disease; D029822:Enterovirus B, Human / Q000502:physiology; D004769:Enterovirus Infections / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D006321:Heart / Q000821:virology; D006632:Histamine / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009205:Myocarditis / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018123:Receptors, Interleukin / Q000235:genetics / Q000502:physiology; D053707:Receptors, Interleukin-12; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
C508438:IL12RB1 protein, human; C508440:Il12rb1 protein, mouse; D007375:Interleukin-1; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4; D006632:Histamine; D007371:Interferon-gamma