PRETREATMENT WITH RECOMBINANT MURINE TUMOR NECROSIS FACTOR cdCACHECTIN AND MURINE INTERLEUKIN 1 a PROTECTS MICE FROM LETHAL BACTERIAL INFECTION

Tumor necrosis factor a/cachectin (TNF/C) is a well-characterized peptide (1) that may, through its diverse effects on cells, mediate many normal host functions, including tissue remodeling and the mobilization of energy reserves required by the infected host (2). In contrast to such beneficial effects, TNF/C has also been shown to have adverse effects on the animal host . It is a principal mediator of the toxic effects of LPS and an important mediator in murine cerebral malaria (3-5). Because of its toxic effects, TNF/C is generally considered to be an abnormal and deleterious response that plays little if any role in host defense against bacterial infection and thus has been considered as a target for therapeutic intervention to ameliorate host toxic responses (4, 6) . Based on these considerations, one might expect that animals that are unable to produce TNF/C in response to bacterial endotoxin would be more resistant to lethal infection than animals that are able to produce TNF/C. The C3H/HeJ mouse is unable to produce TNF/C directly in response to LPS, whereas its congenic pair, the C3H/HeN mouse, does (7). Therefore, we reasoned that the C3H/HeJ mouse would be more resistant than the C3H/HeN mouse to lethal infection with virulent Gram-negative bacteria capable ofcausing bacteremic infection and septic shock. In this study we show, however, that the C3H/HeJ mouse is more susceptible to lethal infection with K1-encapsulated Escherichia coli than is theC3H/HeN mouse, and that pretreatment ofC3H/HeJ mice with a combination of recombinant murine TNF/C and recombinant murine IL-la protects these mice from infection with an inoculum of >20 LD5o.