Release of leukemia inhibitory factor in primate sepsis. Analysis of the role of TNF-alpha.

Abstract

Leukemia inhibitory factor (LIF), a pleiotropic cytokine with many biologic effects overlapping with those of IL-6, has been implicated in the pathogenesis of sepsis. We here analyzed the kinetics of LIF in 13 baboons challenged with a lethal (n=6) or sublethal (n=7) dose of Escherichia coli. In addition, to assess the role of TNF-alpha in the induction of LIF in vivo, seven baboons were studied that had either received a bolus injection of recombinant human TNF-alpha (100 micrograms/kg, n=3), or to whom 15 mg/kg of an anti-TNF mAB before lethal E. coli challenge was administered (n=4). LIF levels increased 2 h after E coli challenge, and reached maximum values at 4 and 8 h after a sublethal (4.4 +/- 1.6 ng/ml) or lethal (40.9 +/- 3.8 ng/ml) dose, respectively. TNF-alpha injection induced a modest rise in LIF concentrations, peaking after 6 h (228 +/- 46 pg/ml). Circulating LIF correlated with plasma levels of IL-6, both after E. coli challenge (Spearman Rank coefficient of correlation (r) = 0.849, p<0.001), as well as upon TNF-alpha injection (r=0.863, p<0.001). Moreover, the E. coli-induced release of either cytokine was reduced 6- to 10-fold after pretreatment with anti-TNF mAb, except in one nonsurviving animal, which exhibited a progressive increase of LIF and IL-6 levels despite the absence of TNF immunoreactivity. These results show that TNF-alpha is an intermediate factor in concerted release of LIF and IL-6 in vivo, and indicate that the enhanced elaboration of these cytokines may predict disease outcome in severe sepsis.