Synergy between tumour necrosis factor alpha and interleukin-1 in the induction of polymorphonuclear leukocyte migration during inflammation

Abstract

Endotoxin is a potent inflammatory stimulus and induces polymorphonuclear leukocyte (PMNL) infiltration into tissues. Macrophage (M phi) derived IL-1 has been proposed as a mediator of this response. TNF alpha is also produced by M phi s in response to endotoxin and both IL-1 and TNF enhance PMNL adhesion to vascular endothelium in vitro. We investigated the activity of recombinant human IL-1 alpha, IL-1 beta, and TNF alpha in inducing PMNL infiltration into the skin of rabbits using a quantitative 51Cr labelled blood leukocyte assay. IL-1 alpha and IL-1 beta induced progressive PMNL accumulation, the 50% maximal response being induced by approximately equal to 20 units. In comparison, TNF alpha even at 100,000 U, induced only mild PMNL accumulations, although IL-1 alpha and TNF alpha were similarly active in inducing PMNL adherence to human umbilical vein endothelium. The human TNF alpha preparation was pyrogenic and induced acute, transient neutropenia in rabbits upon i.v. infusion, IL-1 alpha, IL-1 beta and TNF alpha are often secreted simultaneously by M phi s, therefore we investigated their action in combination. The combination of IL-1 alpha with IL-1 beta was nearly additive in inducing PMNL accumulation, i.e., 87% of predicted result based on the sum of the responses to individual components. The combination of TNF alpha with either IL-1, each in submaximal doses, resulted in 65-125% greater than the additive response. No such effect was observed when these monokines were injected in combination with PMNL chemotactic stimuli. These results indicate a complex interaction between inflammatory monokines in the regulation of PMNL accumulation in vivo.