Immune suppression in polymicrobial sepsis: Differential regulation of Th1and Th2 responses by p38 MAPK

Background. Studies have indicated that a shift from a Th1 to a Th2 respons e occurs that contributes to the late immunosuppression seen during sepsis. However, the mechanism by which this occurs is unknown. In this regard, me diators released in response to sepsis are thought to upregulate a family o f stress-induced mitogen-activated protein kinases (MAPKs), such as JNK, ER K, and p38 MAPK, which may play a role in this process. Materials and methods. To determine the role of MAPK in immune suppression, we induced polymicrobial sepsis in C3H/HeN male mice using cecal ligation and puncture (CLP). Splenic lymphocytes were harvested 24 h post-CLP and st imulated with the T-cell mitogen concanavalinA, and the expression and acti vation of these MAPKs were assessed by Western analysis. To determine the e xtent to which these MAPKs may have an impact on splenic immune function, c ells were pretreated with a 10 mu M concentration of the p38 MAPK inhibitor SB203580 or the MEK inhibitor PD98059 or with DMSO vehicle. The cells were then stimulated with 2.5 mu g/ml of the T-cell mitogen concanavalin A, and cytokine release was then determined (by ELISA). Results. In the lymphocytes from CLP mice no JNK signal was detected, howev er, p38 expression and activation were markedly (P < 0.05, n = 6) increased . In contrast, the expression of activated ERK markedly decreased following septic challenge. The results indicate that p38 MAPK inhibition with SB203 580 suppressed the sepsis-induced augmentation of interleukin-10 release wh ile restoring the suppressed Th1 cytokine interleukin-2 release typically e ncountered following sepsis. Inhibition of ERK had no effect on cytokine re lease. Neither PD98059 nor SB203580 had an effect on interferon gamma relea se or on proliferative capacity. Conclusion. This would indicate that the induction of p38 MAPK activation i n splenocytes contributes to the immunosuppression seen in late sepsis. (C) 2000 Academic Press.