Does Fas ligand or endotoxin contribute to thymic apoptosis during polymicrobial sepsis?

Shock. 1999 Mar;11(3):211-7. doi: 10.1097/00024382-199903000-00010.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Endotoxins / metabolism
  • Endotoxins / pharmacology*
  • Fas Ligand Protein
  • Glucocorticoids / metabolism
  • Hormone Antagonists / pharmacology
  • Ligation
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred Strains
  • Mifepristone / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Sepsis / metabolism*
  • Sepsis / microbiology
  • Sepsis / pathology*
  • Species Specificity
  • Thymus Gland / drug effects
  • Thymus Gland / metabolism
  • Thymus Gland / pathology*
  • bcl-X Protein
  • fas Receptor / metabolism*


  • Bcl2l1 protein, mouse
  • Endotoxins
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Glucocorticoids
  • Hormone Antagonists
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • fas Receptor
  • Mifepristone