Endotoxin, the lipopolysaccharide (LPS) derived from gram-negative bacteria, invokes a wide range of responses in susceptible hosts. It is known that virtually all responses to LPS are mediated by the action of macrophage-derived cytokines (such as interleukin-1 [IL-1], tumor necrosis factor [TNF], and others) which are produced principally by macrophages and maximally within several hours of LPS administration. One manifestation of LPS administration which is not well understood is the phenomenon of "early endotoxin tolerance." In response to a single sublethal injection of LPS, experimental animals become refractory to challenge with a homologous or heterologous LPS preparation 3 to 4 days later. Animals rendered tolerant exhibit mitigated toxicity and a reduced capacity to produce circulating cytokines (i.e., colony-stimulating factor or interferon) in response to the challenge LPS injection. Previous studies have also shown that this state of transient, acquired hyporesponsiveness to LPS is accompanied by a marked increase in the size of cells in the bone marrow which are enriched in numbers of macrophage progenitors. In this study, we examined the capacity of recombinant IL-1 or recombinant TNF or both to induce early endotoxin tolerance and its associated hematopoietic changes. Neither cytokine alone was able to mimic LPS for induction of tolerance. Combined administration of recombinant IL-1 and recombinant TNF doses which were not toxic when administered individually led to synergistic toxicity (as assessed by death or weight loss). However, within a nontoxic range, the two cytokines synergized to induce a significant reduction in the capacity to produce colony-stimulating factor in response to LPS, as well as the characteristic increase in bone marrow cell size and macrophage progenitors shown previously to be associated with LPS-induced tolerance.