DHEA and sepsis


Shock. 2005 Oct;24(4):364-369


DEHYDROEPIANDROSTERONE MODULATES TOLL-LIKE RECEPTOR EXPRESSION ON SPLENIC
MACROPHAGES OF MICE AFTER SEVERE POLYMICROBIAL SEPSIS.

Matsuda A, Furukawa K, Suzuki H, Matsutani T, Tajiri T, Chaudry IH.

*Surgery for Organ Function and Biological Regulation (Department of
Surgery I), Nippon Medical School, Graduate School of Medicine, Tokyo,
113-8603, Japan; and daggerCenter for Surgical Research and Department of
Surgery, University of Alabama, Birmingham, AL.

Toll-like receptors (TLRs) play a pivotal role in the induction of innate
immunity after the transactivation of proinflammatory cytokine genes.
However, the responses of TLRs during severe polymicrobial sepsis have not
been thoroughly examined. Although dehydroepiandrosterone (DHEA), a steroid
hormone, is reported to have an immunomodulatory effect after sepsis, the
mechanism responsible for its salutary is not known. To investigate this,
male ICR/Jcl mice (5-8 weeks old) were subjected to sepsis by cecal
ligation and puncture (CLP) or sham operation. The mice received vehicle or
DHEA (40 mg/kg body weight) subcutaneously immediately after the surgery.
Plasma IL-10 levels and splenic macrophage TNF-alpha production, as well as
the expression levels of CD14, TLR2, and TLR4 mRNAs on splenic macrophages,
were assessed 6 h after the surgery. The results indicate that mice with
sepsis show a marked increase in the plasma IL-10 levels and a decrease in
TNF-alpha production by splenic macrophages. TLR2 and TLR4 mRNA expression
levels after CLP were significantly lower compared with those after the
sham operation. TNF-alpha production and TLR2 and TLR4 mRNA expression on
splenic macrophages are restored with DHEA administration. Furthermore,
administration of DHEA after CLP delayed the mortality of animals. These
results indicate that the anti-inflammatory phase of sepsis induces a
marked down-regulation of TLR expression on splenic macrophages; however,
administration of DHEA resulted in the restoration of TLR2 and TLR4 mRNA
expression.

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