Splenic immune suppression in sepsis: A role for IL-10-induced changes in p38 MAPK signaling

Background. Studies have indicated that following the induction of sepsis, there is a late (24 h) generalized suppression of the immune response which is associated with increased anti-inflammatory mediator release (e.g., IL- 10). However, the mechanisms by which this occurs are unknown. In this rega rd, recent studies indicate that p38 mitogen-activated protein kinase (p38 MAPK) may play a central role in transducing the signals from immunosuppres sive agents which in turn may alter lymphoid cytokine release. The aim of t his study, therefore, was to determine whether the anti-inflammatory mediat or IL-10 alters splenocyte IL-2 and IFN-gamma release, as well as the expre ssion and activation of p38 MAPK in septic animals. Materials and methods. Splenocytes (SPL) (or for some experiments purified T cells) were harvested from mice subjected 24 h earlier to either sepsis b y cecal ligation and puncture (CLP) or Sham-CLP and stimulated with 2.5 mu g concanavalin A (ConA)/ml in the presence or absence of either monoclonal antibody (Mab) to IL-10 (4 mu g/ml) or IgG control. In subsequent studies, sepsis was induced in C57BL/6J and C57BL/6 IL-10 knockout mice, and SPL har vested and stimulated with ConA, SPL cytokine release was measured by ELISA , and the expression and phosphorylation of p38 MAPK were measured by Weste rn analysis. Results. The results indicate that Th1 cytokine (IL-2, IFN-gamma) release w as depressed by sepsis, while p38 MAPK expression and activity were increas ed in SPL as well as in T-cells. Neutralization of IL-10 by in vitro use of anti-IL-10 Mab and in the IL-10 knockout animal restored the Th1 response and caused a downregulation of p38 MAPK expression and activity after CLP. Thus, IL-10 appears to contribute to the increase in p38 MAPK activity and expression and the corresponding suppression of Th1 response seen in late s epsis. (C) 1999 Academic Press.