INTERLEUKIN-6 AUGMENTS NEUTROPHIL CYTOTOXIC POTENTIAL VIA SELECTIVE ENHANCEMENT OF ELASTASE RELEASE

Background. Interleukin-6 (IL-6) appears to be a reliable marker of di sease severity in critically ill patients at risk for inflammatory org an injury such as ARDS and MOF. Debate continues, however, as to wheth er this pleiotropic cytokine acts principally as a proinflammatory or counterregulatory mediator. Because the polymorphonuclear leukocyte (P MN) is a central effector of inflammatory injury, defining the effects of IL-6 on mechanisms of PMN cytotoxicity may be revealing. Previous investigations of PMN release of reactive oxygen species demonstrate t hat IL-6 in concert with other mediators may augment cytotoxicity. We hypothesized that IL-6 alone increases PMN cytotoxic potential through selective enhancement of elastase release. Materials and methods. Iso lated human PMNs were incubated with IL-6 in the physiologic range obs erved in critically ill patients (0.1 to 100 ng/ml) for 10 to 30 min. Selected cells were then activated with fMLP (1 mu M). Elastase releas e was measured by specific cleavage of AAPV-pNA and compared to untrea ted cells and cells activated with formyl-Met-Leu-Phe (fMLP; 1 mu M) a lone. To determine if changes in elastase release might be due to IL-6 induced generation of PAF, WEB 2347 (50 mu M) was preincubated with s elected cells for 20 min. Surface expression of beta(2) integrins was measured by flow cytometry after incubating with labeled antibodies to CD11b and CD18. Results. IL-6 alone at 100 ng/ml augmented basal elas tase release by 116 +/- 41% within 10 min. Doses as low as 0.1 ng/ml s timulated elastase release when the incubation time was increased to 3 0 min. After 30 min of incubation, IL-6 at all doses examined augmente d the elastase release of fMLP-activated cells (increases of 33 to 45% ). WEB 2347 preincubation did not block augmentation of elastase relea se by IL-6 at 10 ng/ml. IL-6 had no effect on surface expression of be ta(2) integrins at 10 ng/ml. Conclusions. IL-6 alone enhances both bas al and fMLP-stimulated elastase release by PMNs. This proinflammatory action on PMNs may help explain the observed correlation between circu lating IL-6 levels and inflammatory organ injury. (C) 1998 Academic Pr ess.