Immunomodulation of coxsackievirus B4-induced pancreatitis.

摘要

Group B coxsackieviruses are enteroviruses belonging to the family Picornaviridae. We have developed a mouse model of chronic pancreatitis by using a virulent variant of coxsackievirus B4, CVB4-V. Infection with CVB4-V results in severe pancreatitis, inflammation of the exocrine pancreas, which can lead to mortality or progress to chronic disease. 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. In the present study, we have shown that exogenous IL-12 protects against lethal infection with CVB4-V. IL-12 treatment also protected the exocrine pancreas of CVB4-V-infected mice from extensive damage and prevented the subsequent development of chronic pancreatitis. Three lines of evidence indicate that the protective effect of IL-12 was mediated by gamma interferon (IFN-gamma). First, administration of IL-12 increased the production of endogenous IFN-gamma by natural killer and natural killer T cells in CVB4-V-infected mice. Second, IFN-gamma deficient mice treated with IL-12 succumbed to infection with CVB4-V. Third, wild-type mice treated with IFN-gamma survived infection with CVB4-V. Despite the antiviral properties of IFN-gamma, we observed no decrease in viral replication in the pancreata of CVB4-V-infected mice treated with IL-12. The data suggest that IL-12-mediated induction of IFN-gamma suppresses immunopathology associated with CVB4-V infection. To elucidate further the mechanism underlying the protective effects of IL-12, we investigated whether exogenous IL-12 altered production of transforming growth factor-beta 1 (TGF-beta1) in CVB4-V-infected mice. Administration of IL-12 induced rapid production of TGF-beta1 in the pancreata of CVB4-V-infected mice. In addition, IFN-gamma deficient mice were unable to rapidly upregulate production of TGF-beta1 in response to exogenous IL-12, suggesting that IFN-gamma was necessary for IL-12-mediated induction of TGF-beta 1. The data suggest that TGF-beta1 is involved in the mechanism underlying the beneficial effects of IL-12 treatment. In the present study, we have also shown that interleukin-10 (IL-10) has a detrimental effect on the outcome of infection. The administration of exogenous IL-12 did not affect IL-10 production during CVB4-V infection. However, IL-12 treatment may overcome the detrimental effects of IL-10 through the induction of IFN-gamma and TGF-beta1.