Anti-IL-10 Therapeutic Strategy Using the Immunomodulator AS101 in Protecting Mice from Sepsis-Induced Death: Dependence on Timing of Immunomodulating Intervention

Abstract

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-α and IL-1β 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-γ 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.

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

“…In mice, plasma levels of IL-10 peak 12 hour after CLP, and the administration of neutralizing anti-IL-10 antibodies to mice with CLP increases mortality [40], suggesting that endogenous IL-10 prevents sepsis. In contrast, IL-10 exerts detrimental effects on bacterial clearance in the later period of sepsis and a nontoxic IL-10 inhibitor increases survival of septic mice [41][42][43]. In our experiments, NKT-cell-mediated IL-10 production by neutrophils enhances C5a generation via inhibition of CD55 expression on neutrophils during sepsis, which is consistent with our previous study [26].…”

The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll‐like receptor‐mediated inflammatory signals

“…The exogenous application of IL-10 can prevent septic shock in mice by inhibiting the synthesis of proinflammatory cytokines, while neutralizing IL-10 inhibited bacterial outgrowth in lungs and improved survival during murine pneumonitis [23,24]. Furthermore, recent studies demonstrated that sepsis is characterized by a biphasic immunological response: an initial hyperinflammatory phase, followed by a hypoinflammatory phase [25,26]. Therefore, it is quite likely that these contradictory observations were attributable to the time of the intervention.…”

Inhibition of Interleukin-10 by the Immunomodulator AS101 Reduces Mesangial Cell Proliferation in Experimental Mesangioproliferative Glomerulonephritis

“…Most of its activities have been primarily attributed to the direct inhibition of the anti-inflammatory cytokine . This immunomodulatory property was found to be crucial for the clinical activities of AS101, demonstrating the protective effects of AS101 in parasite and viralinfected mice models (18), in autoimmune diseases (19), in septic mice (20), and in a variety of tumor models in mice and humans where AS101 had a clear anti-tumoral effect (21)(22)(23). More importantly, AS101 was previously shown to delay the onset of autoimmune manifestations in a murine model of lupus erythematosus, reduce the level of immune complex deposition in the glomeruli, reduce proteinuria, prevent glomerular hypercellularity and mesangial expansion, and reduce the mean glomerular volume of treated mice (19).…”