Release of leukemia inhibitory factor in primate sepsis. Analysis of the role of TNF-alpha
Jansen, P.M.; de Jong, I.W.; Hart, M.; Kim, K.J.; Aarden, L.A.; Hinshaw, L.B.; Taylor, F.B.; Hack, C.E.
Journal of Immunology 156(11): 4401-4407
1996
ISSN/ISBN: 0022-1767 PMID: 8666813 Document Number: 455142
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 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 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 lt 0.001), as well as upon TNF-alpha injection (r = 0.863, p lt 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 the 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.