Exogenous interleukin-12 protects against lethal infection with coxsackievirus B4.
Infections with the group B coxsackieviruses either can be asymptomatic or can lead to debilitating chronic diseases. To elucidate the mechanism by which these viruses cause chronic disease, we developed a mouse model of chronic pancreatitis by using a virulent variant of coxsackievirus B4, CVB4-V. Infection with CVB4-V results in an early, severe pancreatitis, which can lead to mortality or progress to chronic pancreatitis. Chronic pancreatitis, in this model, is due to immunopathological mechanisms. We investigated whether interleukin-12 (IL-12) could modulate the outcome of CVB4-V infection. Eighty-five percent of the infected mice treated with 500 ng of IL-12 survived, whereas all untreated mice succumbed. To understand the mechanism underlying the beneficial effect of IL-12, we investigated the role of gamma interferon (IFN-gamma). Three lines of evidence suggest that the protective effect of IL-12 is due to IFN-gamma. First, administration of IL-12 increased the production of endogenous IFN-gamma in CVB4-V-infected mice. Both NK and NKT cells were identified as the source of IFN-gamma. Second, IFN-gamma knockout mice treated with IL-12 succumbed to infection with CVB4-V. Third, wild-type mice treated with IFN-gamma survived infection with CVB4-V. Due to the antiviral effects of IFN-gamma, we examined whether IL-12 treatment affected viral replication. Administration of IL-12 did not decrease viral replication in the pancreas, but it did prevent extensive tissue damage and the subsequent development of chronic pancreatitis. The data suggest that IL-12 treatment during CVB4-V infection is able to suppress the immunopathological mechanisms that lead to chronic disease.
Potvin
Daniel M
DM
Department of Biomedical Sciences, School of Public Health, State University of New York at Albany, Albany, New York 12237, USA.
Metzger
Dennis W
DW
Lee
William T
WT
Collins
Doris N
DN
Ramsingh
Arlene I
AI
D000818:Animals; D002908:Chronic Disease; D029822:Enterovirus B, Human / Q000472:pathogenicity* / Q000502:physiology; D004769:Enterovirus Infections / Q000401:mortality / Q000473:pathology / Q000517:prevention & control* / Q000821:virology*; D007371:Interferon-gamma / Q000008:administration & dosage / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000473:pathology / Q000821:virology; D010195:Pancreatitis / Q000401:mortality / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D011994:Recombinant Proteins / Q000008:administration & dosage; D014774:Virulence
D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma