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J Surg Res. 2000 Jun 15;91(2):141-6.

Immune suppression in polymicrobial sepsis: differential regulation of Th1 and Th2 responses by p38 MAPK.

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Center for Surgical Research, Brown University School of Medicine, Providence, Rhode Island 02903, USA.



Studies have indicated that a shift from a Th1 to a Th2 response occurs that contributes to the late immunosuppression seen during sepsis. However, the mechanism by which this occurs is unknown. In this regard, mediators released in response to sepsis are thought to upregulate a family of stress-induced mitogen-activated protein kinases (MAPKs), such as JNK, ERK, and p38 MAPK, which may play a role in this process.


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 stimulated with the T-cell mitogen concanavalin A, and the expression and activation of these MAPKs were assessed by Western analysis. To determine the extent to which these MAPKs may have an impact on splenic immune function, cells were pretreated with a 10 microM concentration of the p38 MAPK inhibitor SB203580 or the MEK inhibitor PD98059 or with DMSO vehicle. The cells were then stimulated with 2.5 microg/ml of the T-cell mitogen concanavalin A, and cytokine release was then determined (by ELISA).


In the lymphocytes from CLP mice no JNK signal was detected, however, 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 SB203580 suppressed the sepsis-induced augmentation of interleukin-10 release while restoring the suppressed Th1 cytokine interleukin-2 release typically encountered following sepsis. Inhibition of ERK had no effect on cytokine release. Neither PD98059 nor SB203580 had an effect on interferon gamma release or on proliferative capacity.


This would indicate that the induction of p38 MAPK activation in splenocytes contributes to the immunosuppression seen in late sepsis.

[Indexed for MEDLINE]

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