RELEASE OF LEUKEMIA INHIBITORY FACTOR IN PRIMATE SEPSIS - ANALYSIS OFTHE ROLE OF TNF-ALPHA

Leukemia inhibitory factor (LIF), a pleiotropic cytokine with many bio logic effects overlapping with those of IL-6, has been implicated in t he 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 r eceived a bolus injection of recombinant human TNF-alpha (100 mu g/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 sublet hal (4.4 +/- 1.6 ng/ml) or lethal (40.9 +/- 3.8 ng/ml) dose, respectiv ely, 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 coe fficient of correlation (r) = 0.849, p < 0.001), as well as upon TNF-a lpha injection (r = 0.863, p < 0.001), Moreover, the E. coli-induced r elease 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 intermed iate factor in the concerted release of LIF and IL-6 in vivo, and indi cate that the enhanced elaboration of these cytokines may predict dise ase outcome in severe sepsis.