Inhibition of Macrophage-activating Cytokines is Beneficial in the Acute Septic Response

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Abstract
Interferon-gamma and other cytokines enhance macrophage (M phi) antimicrobial function and have been considered for therapeutic use in sepsis. Systemic sequelae of macrophage activation, however, are unclear. This study examined the effects of M phi activating cytokines (interferon-gamma [IFN-gamma] and interleukin-4 [IL-4]) and monoclonal antibodies directed against these cytokines in modulating the acute septic response. CFW/Swiss Webster mice (n = 345) received endotoxin (lipopolysaccharide [LPS]: 60 mg/kg body weight intraperitoneally) and were randomized to five treatment groups: IFN-gamma (10(4) units), IL-4 (10(4) units), IgG1 isotype antibody (TRFK5: 200 micrograms), anti-IFN-gamma (200 micrograms), or anti-IL-4 (200 micrograms) monoclonal antibodies (MAbs) given simultaneously or 2 hours after LPS. Animals were divided into two groups and studied for mortality or measurement of peritoneal M phi superoxide anion release (O2-), tumor necrosis factor (TNF), and IL-6 production 6 hours after administration of LPS +/- experimental regimens. Serum TNF and IL-6 also were assessed at 2 and 4 hours after LPS, respectively. Administration of LPS resulted in a 27% survival compared with 10% in the IFN-gamma and 13% in the IL-4 groups. Treatment with anti-IFN-gamma offered protection against LPS lethality (93%-100% survival, p less than 0.001 vs. other groups) when given either simultaneously or 2 hours after LPS. Anti-IFN-gamma also significantly decreased PM phi O-2 and TNF release. Thus anti-IFN-gamma may have an important role in the modulation of the acute septic response.