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

Recent studies have shown that with the onset of sepsis there is an increase in apoptosis (A(o)) 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 A(o) 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 %A(o)+ seen in thymocytes of CLP C3H/HeN mice was associated with either no change (12 h) or a decrease in %Fast+ 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 %A(o)+ increased after CLP in both ETX-tolerant and ETX-tolerant/FasL-deficient mice. Furthermore, ii ETX-tolerant/FasL-deficient CLP animals were administered the steroid receptor antagonist RU-38486 (s.c., immediately after CLP) the increase in A 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 A(o) 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.