title: IL-10 mediation of activation-induced TH1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis.
abstract: Recent studies suggest that increased activation-induced lymphocyte apoptosis (AICD) is detected in mouse splenocytes during polymicrobial sepsis which may contribute to lymphocyte immune dysfunction [i.e., decreased interleukin (IL-)2 and interferon-gamma (IFN-gamma) production] leading to the associated morbidity seen in those animals. Thus, we wanted to examine the hypothesis that immune suppressive agents, such as IL-4, IL-10 or prostaglandin E2(PGE2), known to be elevated in septic animals, also contribute to this increase in AICD. Here we demonstrate that the inclusion of monoclonal antibody (mAb) to IL-10, but not anti-IL-4 or ibuprofen (IBU), blunted this sepsis induced increase in splenocyte AICD. Additionally, septic mice deficient in the IL-10 gene product (-/-) showed neither an increase in AICD nor a loss of IL-2/IFN-gamma release capacity. Interestingly, mAb to IL-10 did not altered the extent of AICD in a Th2-cell line, but exogenous IL-10 did potentiate Th1-like cell line AICD. This was consistent with the finding that the increased AICD seen in septic mouse splenocytes was restricted largely to the CD4+ cells producing IL-2 (Th1-cells) and that mAb to IL-10 treatment suppressed this change. Furthermore, IL-10 appears to mediate its AICD effect by upregulation of the Fas receptor and Fas receptor signaling protein components, but not by altered expression of Bcl/Bax/Bad family members, in septic mouse splenocytes. To the extent that these processes contribute in a pathological fashion to the animal's capacity to survive sepsis we have previously observed that in vivo post-treatment of mice with mAb IL-10 markedly attenuated septic mortality. Collectively, these data indicate that in the septic mouse the Th2 cytokine IL-10 not only serves to actively induce Th1 lymphocyte immune dysfunction but also plays a role in their apoptotic depletion. These processes in turn appear to contribute to the animal's inability to ward off lethal septic challenge.
authors: Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA. AAYALA@LIFESPAN.org
authors: A
authors: A
authors: Ayala
authors: C S
authors: CS
authors: Chung
authors: G Y
authors: GY
authors: Song
authors: I H
authors: IH
authors: Chaudry
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D015232:Dinoprostone / Q000276:immunology; D005434:Flow Cytometry; D017353:Gene Deletion; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019014:fas Receptor / Q000235:genetics
chemical_list: C494820:Bad protein, mouse; C494827:Bax protein, mouse; D002352:Carrier Proteins; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019014:fas Receptor; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D015232:Dinoprostone