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* C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel;
Departments of Nephrology and Pathology, Rabin Medical Center, Golda Campus, Petah Tikva, Israel; and
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
The role of IL-10 in experimental sepsis is controversial. The
nontoxic immunomodulator, ammonium
trichloro(dioxoethylene-o,o')tellurate (AS101) has been previously
shown to inhibit IL-10 expression at the transcriptional level. In this
study, we show that in mice subjected to cecal ligation and puncture
(CLP), treatment with AS101 12 h after, but not before, CLP
significantly increased survival of septic mice. This was associated
with a significant decrease in serum IL-10 and in IL-10 secretion by
peritoneal macrophages 24–48 h after CLP. At that time, the ability of
these cells to secrete TNF-
and IL-1
was restored in
AS101-treated mice. The increased survival of AS101-treated mice was
due to the inhibition of IL-10, since cotreatment with murine rIL-10
abolished the protective activity of AS101. AS101 increased class II Ag
expression on peritoneal macrophages, severely depressed in control
mice, while it did not affect the expression of class I Ags. This was
accompanied by a significant elevation in the level of IFN-
secreted
by splenocytes. Moreover, AS101 ameliorated bacterial clearance in the
peritoneum and blood and decreased severe multiple organ damage, as
indicated by clinical chemistry. Furthermore, myeloperoxidase levels in
the liver and lung of AS101-treated mice, an indirect means of
determining the recruitment of neutrophils, were significantly
decreased. We suggest that nontoxic agents such as AS101, with the
capacity to inhibit IL-10 and stimulate macrophage functions, may have
clinical potential in the treatment of sepsis, provided they are
administered during the phase of sepsis characterized by immune
suppression.
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