Pretreatment with recombinant murine tumor necrosis factor alpha/cachectin and murine interleukin 1 alpha protects mice from lethal bacterial infection.

Abstract

Tumor necrosis factor/cachectin (TNF/C) is the principal mediator of bacterial endotoxin-induced shock and death. We found that the C3H/HeJ mouse, which is less able to produce TNF/C in response to endotoxin, has a 1,000-fold greater susceptibility to lethal infection with Escherichia coli than the TNF-responsive congenic mouse, C3H/HeN. This surprising finding suggested that this lethal peptide may also be involved in host protection. To test this hypothesis we pretreated the C3H/HeJ mouse with a combination of recombinant murine TNF/C-alpha and IL-1 alpha. This combination protected these mice against an intraperitoneal bacterial challenge of greater than 20 LD50S (nearly 2 x 10(2) CFU) that grew to a level of greater than 10(7) CFU/ml of blood and per gram of liver in untreated mice. This suggests a significant role for these cytokines in host defenses against invasive infections that require bacterial replication within the host. These protective mechanisms may not be important for less virulent organisms. These findings may have important implications for the proposed use of anti-TNF/C agents in the treatment of septic shock.

The importance of a lipopolysaccharide-initiated, cytokine-mediated host defense mechanism in mice against extraintestinally invasive Escherichia coli.

“…M-CSF, IL-1, and TNF each activated these peritoneal macrophages in a dose-dependent manner. As might be anticipated from the protective effects of this cytokine combination in vivo (18), combinations of IL-I and TNF have synergistic effects when used at concentrations that were ineffective when used alone.…”

“…We have previously shown that C3H/HeJ mice that are blocked in their ability to respond normally to LPS are highly susceptible to lethal infection after challenge with low levels of Ki-encapsulated bacteria possessing a smooth LPS phenotype (18). The administration of the combination recombinant murine TNF-a and IL-a, however, protected these mice from > 10 LD50 bacterial challenge.…”

Critical Role of Lipopolysaccharide-Binding Protein and CD14 in Immune Responses against Gram-Negative Bacteria

“…Conversely, treatment with TNF-␣ improved survival of mice injected with S. typhimurium or undergoing cecal ligation puncture (22,23). Importantly, LPS-hyporesponsive C3H/HeJ mice were found to be more susceptible to lethal infection with Escherichia coli than normal LPS-responsive mice, a defect that was corrected by administration of TNF-␣ (24).…”

IL-18 Levels and the Outcome of Innate Immune Response to Lipopolysaccharide: Importance of a Positive Feedback Loop with Caspase-1 in IL-18 Expression

“…3B), more bacterial regrowth was observed in mice treated with higher IL-18 doses, but not 5 ng IL-18, suggesting impairment of bactericidal mechanisms at the higher doses. Given our previous finding of impaired bactericidal activity following seemingly small changes in cytokine balance (47), it is attractive to speculate that the inflammatory network induced by LPS requires precise regulation such that changes in any one component may compromise the ability to defend against bacterial infection. We are currently studying the mechanism by which high doses of IL-18 impair the bactericidal activity.…”