G Y Song1, C S Chung, I H Chaudry, A Ayala. 1. Center for Surgical Research, Brown University School of Medicine, Providence, Rhode Island 02903, USA.
Abstract
BACKGROUND: 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. 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 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). RESULTS: 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. CONCLUSION: This would indicate that the induction of p38 MAPK activation in splenocytes contributes to the immunosuppression seen in late sepsis. Copyright 2000 Academic Press.
BACKGROUND: 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. 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 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). RESULTS: In the lymphocytes from CLPmice 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. CONCLUSION: This would indicate that the induction of p38 MAPK activation in splenocytes contributes to the immunosuppression seen in late sepsis. Copyright 2000 Academic Press.
Authors: Zoltán H Németh; Balázs Csóka; Jeanette Wilmanski; Dazhong Xu; Qi Lu; Catherine Ledent; Edwin A Deitch; Pál Pacher; Zoltán Spolarics; György Haskó Journal: J Immunol Date: 2006-05-01 Impact factor: 5.422
Authors: György Haskó; Balázs Csóka; Balázs Koscsó; Rachna Chandra; Pál Pacher; Linda F Thompson; Edwin A Deitch; Zoltán Spolarics; László Virág; Pál Gergely; Rolando H Rolandelli; Zoltán H Németh Journal: J Immunol Date: 2011-09-14 Impact factor: 5.422
Authors: Alfred Ayala; Yanli Ding; Rebecca J Rhee; Lesley A Doughty; Patrician S Grutkoski; Chun-Shiang Chung Journal: Rec Res Dev Immunol Date: 2003-01-12
Authors: Balázs Csóka; Zoltán H Németh; Partha Mukhopadhyay; Zoltán Spolarics; Mohanraj Rajesh; Stephanie Federici; Edwin A Deitch; Sándor Bátkai; Pál Pacher; György Haskó Journal: PLoS One Date: 2009-07-29 Impact factor: 3.240