Interleukin-8-induced suppression of polymorphonuclear leukocyte apoptosis is mediated by suppressing CD95 (Fas/Apo-1) Fas-1 interactions

Background, Neutrophil apoptosis is crucial in the resolution of inflammation. The role of interleukin (IL)-8 in neutrophil apoptosis has not been previously, studied; we hypothesized that in addition to its role as a chemoattractant, IL-8 would regulate polymorphonuclear leukocyte (PMN) apoptosis. Methods, PMNs were adhered to plastic during hypoxia or normoxia and treated with IL-8 dosages of 0 to 1000 ng/mL. Apoptosis was assessed by cellular histology and the TUNEL assay. For receptor inhibition, blocking antibodies to IL-8 receptors in the presence of IL-8 were added. Apoptosis of PMNs treated with anti;Fas antibody +/- IL-8 was also analyzed. Results, After treatment with 100 ng/mL IL-8, apo;otosis was decreased from an average of 39.1% to 9.3%. Inhibition of IL-8RA was able to restore apoptosis to 58.4%. Western analysis showed that with IL-8, there was a marginal decrease of total Fas protein, whereas Fas ligand was increased. After incubation with an apoptosis inducing Fas antibody, average PMN apoptosis was 42.3%, whereas Fas antibody plus IL-8 reduced apoptosis to 9.5%. Conclusions. IL-8 not only promotes the inflammatory response by recruiting PMNs but also acts to suppress apoptosis mainly through the IL-8RA in an oxygen tension independent manner The reduction in apoptosis is associated with changes in Fas and Fast where the presence of IL-8 suppresses the proapoptotic function of Fas-FasL interactions.