The cooperative effects of TNF-α and IFN-γ are determining factors in the ability of IL-10 to protect mice from lethal endotoxemia

Abstract

Recent studies have demonstrated that interleukin-10 (IL-10) has the capacity to protect mice from the lethal effects of endotoxin. In this investigation, we have examined the ability of IL-10 to protect both normal mice and Corynebacterium parvum-primed mice against endotoxin lethality. In the overwhelming majority of experiments, recombinant murine IL-10 (rMuIL-10) and recombinant human IL-10 (rHuIL-10) did not protect normal BALB/cJ mice from lipopolysaccharide (LPS)-induced lethality at doses up to 10 micrograms/mouse. Despite their inability to protect, both IL-10 preparations were highly effective in preventing the increase in serum tumor necrosis factor alpha (TNF-alpha) that occurred in response to the lethal dose of LPS. Moreover, a neutralizing antibody against TNF-alpha gave only partial protection when administered alone to BALB/cJ mice. Treatment with a combination of neutralizing antibodies against TNF-alpha and interferon-gamma (IFN-gamma) resulted in complete protection. In contrast to BALB/cJ mice, normal BDF1 mice were protected from lethal endotoxemia by treatment with both rMuIL-10 and rHuIL-10. However, IL-10 did not protect C. parvum-primed BDF1 against LPS lethality even though it caused a reduction in the LPS-induced serum TNF-alpha response in C. parvum-primed mice as well as in normal BDF1 mice. Neutralizing antibodies against TNF-alpha and IFN-gamma were protective when administered alone to normal BDF1 mice, as previously demonstrated in C. parvum-primed mice. These findings suggest that lethal endotoxemia is a result of the cooperative activities of TNF-alpha and IFN-gamma in normal mice of the BALB/cJ and BDF1 strains as well as in C. parvum-primed BDF1 mice. IL-10 appears to be less effective in protecting mice from lethal endotoxemia when cooperation between IFN-gamma and TNF-alpha is facilitated by high-level production of the cytokines as in C. parvum-primed mice or when there is evidence of strong synergy between them as in normal BALB/cJ mice.

Cytokine Gene Expression in Innately Susceptible BALB/c Mice and Relatively Resistant C57BL/6 Mice during Infection with VirulentBurkholderia pseudomallei

“…Because IL-10 is a potent anti-inflammatory cytokine, it is possible that IL-10 has an important suppressive immunoregulatory role in the early stages of B. pseudomallei infection. Among its many activities, IL-10 inhibits the generation of nitrogen radicals in macrophages and suppresses proinflammatory cytokine production (37,45). In view of the results of the present study, it may be argued that the earlier appearance of IL-10 in spleen of BALB/c mice could lead to a preferential Th2-type cytokine response, diminished cell-mediated immunity, and increased host susceptibility.…”

“…Simultaneous increases in the levels of mRNA for IL-10 and IFN-␥, as observed in this study, are consistent with recent reports on cytokine responses to other intracellular pathogens (7,19,37). Such studies have suggested a potential beneficial role of IL-10 for increased host resistance during intracellular infection, despite the known anti-inflammatory actions of this cytokine (45). A cytokine pattern involving high levels of IL-10 and IFN-␥ without an increase in IL-2 or IL-4 has recently been coined the Tr1-type profile (22,30).…”

Involvement of intrasinusoidal hemostasis in the development of concanavalin a-induced hepatic injury in mice

“…2,5,6 In the present study, the pretreatment of mice with either anti-TNF-␣ MAb or anti-IFN-␥ MAb moderately, but not significantly, improved the hepatic microcirculation, whereas the combined use of two MAbs, even in half doses, increased the blood flow much more than did the controls and the treatment with a single MAb, which is indicative of the synergistic action of TNF-␣ with IFN-␥ for the induction of hemostasis. Cooperative activities of these cytokines have been reported also in the lethal endotoxemia 28 and cytokine-induced ischemic necrosis in many organs, including the lungs and liver. 27 Although it is unclear how TNF-␣ and IFN-␥ contribute to the hemostasis, they probably induce sinusoidal alterations such as endothelial swelling [15][16][17] and serotonin-mediated sinusoidal constriction 19,29 (IFN-␥ releases serotonin from the platelets 20 ).…”

Endogenously opsonized particles divert prostanoid action from lethal to protective in models of experimental endotoxemia.

“…We are unaware of any experimental or clinical data other than these that suggest successful intervention is possible in the later stages of the systemic inflammatory response (29). Current effective experimental treatment modalities for sepsis require either prophylactic treatment (30,31) or administration at the time of endotoxin challenge (32)(33)(34). Unlike these sepsis therapies, treatment with PGE1 plus liposomes takes advantage of the activation of professional phagocytes and thus exploits the natural cellular immune response to septic insult.…”