IL-10 has an important regulatory function in endotoxin-induced systemic inflammatory responses. IL-10 -/- mice are exceedingly susceptible to endotoxin and to the induction of the Shwartzman reaction (65). Similarly, neutralization of endogenous IL-10 by administration of antibodies renders normal mice more susceptible to the effects of endotoxin, increases the amount of TNF released, and greatly increases mortality. Conversely, administration of IL-10 dose dependently reduced the mortality of endotoxemia owing to a reduction of TNF production (66). Administration of recombinant hIL-10 to baboons strongly reduced the release of proinflammatory cytokines in baboons challenged with a sublethal dose of endotoxin. However, in this model, IL-10 administration did not prevent activation of several more peripheral inflammatory pathways, such as activation of the coagulation and fibrinolytic systems, and the effect on granulocyte degranulation was only modest (67). In a localized model of gram-negative infection induced by ligation and puncture of the cecum in C57Bl/6 mice, IL-10 was rapidly (within 1 h) induced in various distant organs, and serum levels of IL-10 became increased 2 hs after the insult (68). In this model, administration of IL-10-neutralizing antibodies caused a significant increase of mortality. It should be noted that IL-10 is not protective in all models of bacterial infection. For example, in murine pneumococcal pneumonia, administration of IL-10 impairs the host's ability to clear bacteria and results in an increase of bacteria in blood and greater mortality (69). Conversely, in this model, neutralization of IL-10 lowers bacterial counts and improves survival. In conclusion, in inflammatory responses induced by endotoxin, gram-negative or gram-positive bacteria, IL-10 generally downregulates the release of proinflammatory cytokines. In severe generalized inflammatory responses, this effect may be beneficial and result in a reduction of mortality. However, in some models, bacterial clearance is dependent on the activities of proinflammatory cytokines (IFN-y, IL-1P, TNF-a), and, in these circumstances, IL-10 may increase mortality as a consequence of overwhelming bacteremia.
In a T-lymphocyte-dependent model of generalized inflammation induced by injection of staphylococcal enterotoxin B (SEB), IL-10 was rapidly produced by CD4+ T lymphocytes. This endogenous release of IL-10 counteracted the release of IFN-y and IL-2 (but not of TNF-a), and neutralizing IL-10 antibodies caused increased (IFN-y-dependent) mortality (70).
Depending on the route of priming (intranasal or intraperitoneal), mice develop predominantly Th1- or Th2-mediated inflammatory responses to pulmonary challenge with Aspergillus fumigatus antigens. In IL-10 -/- mice, such allergic responses are exaggerated and associated with significantly higher concentrations of IL-4, IL-5, and IFN-y (71). Hence, IL-10 can suppress both Th1 and Th2 responses to Aspergillus antigens.
The role of IL-10 in Chagas' disease is complex: Natural resistance of mice against infection with Trypanosoma cruzei is known to be associated with high levels of IFN-y and a low production rate of IL-10 (72). Indeed, infection of IL-10 -/- mice with T. cruzei resulted in a higher production of TNF-a, IFN-y, and IL-12 that was associated with a lower parasite burden (73). In this model, this resulted in an earlier mortality of IL-10 -/- mice that could be reversed by administration of anti-CD4 antibodies. Hence, it seemed that the early mortality due to T. cruzei infection was caused by cyto-kines derived from CD4+ T lymphocytes (e.g., IL-12-induced IFN-y). Apparently in contrast with these findings, it was demonstrated that IL-10-deficient macrophages had a defect in intracellular killing of T. cruzei because of insufficient induction of nitrous oxide, which could be corrected by IL-10 supplementation (74). A potential explanation for these findings is that, although IL-10 can upregulate NO production in macrophages, in vivo this effect is offset by an important counterregulatory effect on IFN-y production (another potent inducer of NO synthesis). In Plasmodium berghei induced cerebral malaria in mice, which is known to be dependent on TNF-a production, IL-10 had a protective effect (75).
In intestinal-derived candidiasis in mice, administration of IL-4 and IL-10 caused a Th2 shift in the Peyer's patches, and this was associated with a greatly increased susceptibility and fatal outcome of disease (76). On the other hand, exogenous IL-10 did not influence outcome when administered to mice that had established cellular (Th1-mediated) immunity to Candida and were rechallenged with the organism.
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