BACKGROUND/AIMS: Liver natural killer 1.1 antigen (NK1)+ T cells and IL-4 play a crucial role in concanavalin-A (Con-A)-induced hepatic injury in mice, and a T helper (Th) 2 immune response was thus suggested to be involved. This study was designed to examine the effect of bacterial lipopolysaccharide (LPS), a strong inducer of a Th 1 immune response, on Con-A hepatic injury and also to clarify further the cytokine milieu of Con-A hepatitis. METHODS: LPS were injected into mice before Con-A injection to evaluate the effect on hepatic injury. The effect of the pretreatment with various T1 and Th2 cytokines or anti-cytokine antibodies on Con-A hepatitis was also examined. RESULTS: LPS in quantities > or = 500 ng/mouse, when injected 24 h before Con-A injection, abrogated the Con-A-induced elevation of transaminases, hepatocyte destruction and serum IL-4 elevation. This LPS inhibitory effect was blocked when the mice were injected with either anti-IL-6 antibody before LPS injection or IL-4 before Con-A injection. IL-6, but neither IL-10 nor IL-12 pretreatment suppressed Con-A-induced IL-4 production and hepatitis. NK1+ T cells produced IL-4 while both NK1+ T cells and NK1- T cells produced IFN-gamma. Not only anti-IL-4 antibody but also the anti-IFN-gamma antibody pretreatment inhibited Con-A hepatitis. However, although the anti-IL4 antibody suppressed IL-4 alone, the anti-IFN-gamma Ab unexpectedly inhibited both IFN-gamma and IL-4 elevation, while IL-4 injection evoked a moderate Con-A hepatitis even in the anti-IFN-gamma antibody-treated mice. Furthermore, the IL-4 mutant mice did not develop Con-A hepatitis. CONCLUSION: LPS inhibited Con-A hepatitis by inducing IL-6 and thereby inhibited IL-4 synthesis from NK1+ T cells. Although both IL-4 and IFN-gamma were required for the full induction of Con-A hepatic injury, exogenous IL-4 evoked a moderate Con-A hepatitis, even in the absence of IFN-gamma.
BACKGROUND/AIMS: Liver natural killer 1.1 antigen (NK1)+ T cells and IL-4 play a crucial role in concanavalin-A (Con-A)-induced hepatic injury in mice, and a T helper (Th) 2 immune response was thus suggested to be involved. This study was designed to examine the effect of bacterial lipopolysaccharide (LPS), a strong inducer of a Th 1 immune response, on Con-A hepatic injury and also to clarify further the cytokine milieu of Con-A hepatitis. METHODS:LPS were injected into mice before Con-A injection to evaluate the effect on hepatic injury. The effect of the pretreatment with various T1 and Th2 cytokines or anti-cytokine antibodies on Con-A hepatitis was also examined. RESULTS:LPS in quantities > or = 500 ng/mouse, when injected 24 h before Con-A injection, abrogated the Con-A-induced elevation of transaminases, hepatocyte destruction and serum IL-4 elevation. This LPS inhibitory effect was blocked when the mice were injected with either anti-IL-6 antibody before LPS injection or IL-4 before Con-A injection. IL-6, but neither IL-10 nor IL-12 pretreatment suppressed Con-A-induced IL-4 production and hepatitis. NK1+ T cells produced IL-4 while both NK1+ T cells and NK1- T cells produced IFN-gamma. Not only anti-IL-4 antibody but also the anti-IFN-gamma antibody pretreatment inhibited Con-A hepatitis. However, although the anti-IL4 antibody suppressed IL-4 alone, the anti-IFN-gamma Ab unexpectedly inhibited both IFN-gamma and IL-4 elevation, while IL-4 injection evoked a moderate Con-A hepatitis even in the anti-IFN-gamma antibody-treated mice. Furthermore, the IL-4 mutant mice did not develop Con-A hepatitis. CONCLUSION:LPS inhibited Con-A hepatitis by inducing IL-6 and thereby inhibited IL-4 synthesis from NK1+ T cells. Although both IL-4 and IFN-gamma were required for the full induction of Con-A hepatic injury, exogenous IL-4 evoked a moderate Con-A hepatitis, even in the absence of IFN-gamma.
Authors: Patricia Castillo-Dela Cruz; Alanna G Wanek; Pawan Kumar; Xiaojing An; Waleed Elsegeiny; William Horne; Adam Fitch; Ansen H P Burr; Kathyayini P Gopalakrishna; Kong Chen; Barbara A Methé; Scott W Canna; Timothy W Hand; Jay K Kolls Journal: Cell Rep Date: 2019-11-19 Impact factor: 9.423