title: Does Fas ligand or endotoxin contribute to thymic apoptosis during polymicrobial sepsis?
abstract: Recent studies have shown that with the onset of sepsis there is an increase in apoptosis (Ao) in the thymus, mediated in part by steroids, which may contribute to a loss of T-cell progenitors, thereby, reducing immune functions. However, reports also suggest that these steroid effects could be mediated by Fas ligand (FasL) and/or by endotoxin (ETX). Thus, our study was to determine: 1) if polymicrobial sepsis (cecal ligation and puncture; CLP) alters thymocyte Fas antigen/receptor (Fas+) expression and 2) if the increase in Ao in septic ETX-sensitive C3H/HeN mice is seen in thymocytes from ETX-tolerant, C3H/HeJ, or the FasL-deficient/ETX-tolerant, C3H/HeJ-FasL(gld), male mouse strains subjected to CLP or sham-CLP (Sham) 12 or 24 h before they were killed. The results of flow cytometric analysis indicated that increased %Ao+ seen in thymocytes of CLP C3H/HeN mice was associated with either no change (12 h) or a decrease in %Fas+ expression at 24 h, although the %Bcl-2+ (an antiapoptotic protein) cells was depressed at both times. Additional studies examining C3H/HeJ or C3H/HeJ-FasL(gld) mice subjected to CLP show that as with the ETX-sensitive mouse, thymocyte Fas and Bcl-2 antigen expression as well as Bcl-2/Bcl-X(L/S) mRNA levels decreased although the %Ao+ increased after CLP in both ETX-tolerant and ETX-tolerant/FasL-deficient mice. Furthermore, if ETX-tolerant/FasL-deficient CLP animals were administered the steroid receptor antagonist RU-38486 (s.c., immediately after CLP) the increase in Ao was markedly attenuated, along with restoration of the percentage of cells expressing Bcl-2 and Fas antigen as well as Bcl-2/Bcl-X(L/S) mRNA levels. Thus, we concluded that increased septic thymocyte Ao is not regulated through either Fas mediated pathway or ETX, but is a result of the release of endogenous steroids possibly acting directly or indirectly on Bcl-2 expression.
authors: Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence 02903, USA.
authors: A
authors: A
authors: Ayala
authors: Y X
authors: YX
authors: Xu
authors: C S
authors: CS
authors: Chung
authors: I H
authors: IH
authors: Chaudry
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004731:Endotoxins / Q000378:metabolism / Q000494:pharmacology*; D053222:Fas Ligand Protein; D005938:Glucocorticoids / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D008026:Ligation; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D015735:Mifepristone / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D018805:Sepsis / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D013045:Species Specificity; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051020:bcl-X Protein; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C494812:Bcl2l1 protein, mouse; D004731:Endotoxins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005938:Glucocorticoids; D006727:Hormone Antagonists; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; D015735:Mifepristone