Anti-IL-10 therapeutic strategy using the immunomodulator AS101 in protecting mice from sepsis-induced death: dependence on timing of immunomodulating intervention.
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-alpha and IL-1beta 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-gamma 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.
Kalechman
Yona
Y
C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Gafter
Uzi
U
Gal
Rivka
R
Rushkin
Galit
G
Yan
Donghong
D
Albeck
Michael
M
Sredni
Benjamin
B
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001419:Bacteria / Q000187:drug effects; D002432:Cecum; D016207:Cytokines / Q000097:blood; D004334:Drug Administration Schedule; D005030:Ethylenes / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009102:Multiple Organ Failure / Q000209:etiology / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D009195:Peroxidase / Q000378:metabolism; D011677:Punctures; D018805:Sepsis / Q000276:immunology / Q000382:microbiology / Q000401:mortality* / Q000517:prevention & control*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis
D000276:Adjuvants, Immunologic; D016207:Cytokines; D005030:Ethylenes; D016753:Interleukin-10; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D007371:Interferon-gamma; D009195:Peroxidase