EFFECT OF CYTOKINES IN HOST DEFENSE AND INFLAMMATION

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For several years the LHD has been characterizing the inflammatory response associated with superficial skin lesions raised on the forearms of both normal volunteers and patients with various disorders of inflammation. The LHD recently determined that human exudative neutrophils from normal subjects have very high levels of cell associated IL-8 (6900pg/106 PMNs) and spontaneouly release Il-8 during culture. In contrast, freshly isolated peripheral blood PMNs contain very low levels of IL-8 (38 pg/106 PMNs). Incubation of peripheral blood PMNs at 37 degrees C with thapsigargin, an inhibitor of endoplasmic reticulum Ca2+-ATPase, causes a sustained elevation in [Ca2+]i (attributable to extracellular calcium influx) and is associated with increased expression of IL-8 mRNA and increased production and release of IL-8 from isolated peripheral blood neutrophils. Levels of cell-associated IL-8 are comparable to those observed in exudative neutrophils. In addition, IL-8 production by thapsigargin is inhibited by therapeutic concentrations of cyclosporin A. These data suggest that production of IL-8 by migrating neutrophils represents an autocrine mechanism for recruitment of additional neutrophils to inflammatory foci. Furthermore, cyclosporin A may may have important uses as an antiinflammatory agent by virtue of its effect on IL-8 synthesis. In related studies, we have shown that soluble fibrinogen synergizes with the chemotactic peptide fmet-leu-phe (5nM), to induce IL-8 production. A higher, activating dose of fmet-leu-phe (100nM) is not effective in inducing IL-8 production. These studies with fibrinogen have prompted investigation of the induction of IL-8 in neutrophils adherent to extracellular matrix proteins as well as neutrophils undergoing chemotaxis in vitro. Preliminary evidence suggests that adherence of neutrophils to fibrinogen-coated plates causes induction of IL-8 production.