MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis.
Although studies indicate that a shift from a Th1 to a Th2 response contributes to a marked suppression of cell-mediated immunity during sepsis, the mechanism by which this occurs remains unknown. Given that the mitogen-activated protein kinase (MAPK) p38 plays a critical role in the activation and function of immune cells, the aim of this study was to determine the contribution of MAPK p38 activation to the immune dysfunction seen in polymicrobial sepsis. To study this, polymicrobial sepsis was induced in C3H/HeN male mice by cecal ligation and puncture (CLP). Splenic lymphocytes and purified T cells were harvested 24 h post-CLP, pretreated with the specific MAPK p38 inhibitor SB-203580, and then stimulated with a monoclonal antibody against the T cell marker CD3. The results indicate that interleukin (IL)-2 release is markedly depressed while the release of the immunosuppressive mediator, IL-10, as well as mRNA levels of IL-10 and IL-4, are augmented after CLP. Inhibition of MAPK p38 suppressed in vitro IL-10 levels as well as IL-10 and IL-4 gene expression while restoring the release of IL-2. To determine whether these in vitro findings could be translated to an in vivo setting, mice were given 100 mg of SB-203580/kg body wt or saline vehicle (intraperitoneal) at 12 h post-CLP. Examination of ex vivo lymphocyte responsiveness indicated that, as with the in vitro finding, septic mouse Th1 responsiveness was restored. In light of our recent finding that delayed in vivo SB-203580 treatment also improved survival after CLP, we believe that these results not only illustrate the role of MAPK p38 in the induction of immunosuppressive agents in sepsis but demonstrate that SB-203580 administration after the initial proinflammatory state of sepsis significantly prevents the morbidity from sepsis.
Song
G Y
GY
Division of Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, Rhode Island 02903, USA.
Chung
C S
CS
Chaudry
I H
IH
Ayala
A
A
D000818:Animals; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007108:Immune Tolerance / Q000502:physiology*; D007109:Immunity / Q000502:physiology; D007111:Immunity, Cellular; D007239:Infections / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008221:Lymphoid Tissue / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D007376:Interleukin-2; D007527:Isoenzymes; D011725:Pyridines; D016753:Interleukin-10; D015847:Interleukin-4; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580