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,
* Bonfils Blood Center, and the Departments of
Medicine,
Surgery, and Pediatrics, University of Colorado School of Medicine, Denver
Correspondence: Christopher C. Silliman, M.D., Ph.D., Research Department, Bonfils Blood Center, 717 Yosemite Circle, Denver, CO 80230. E-mail: chistopher.silliman{at}uchsc.edu
Patients with sepsis and acute lung injury have increased interleukin (IL)-18 levels systemically. We hypothesize that IL-18 stimulates neutrophils (PMNs) at physiologic concentrations. IL-18 primed the oxidase at 15 min (10–100 ng/ml), 30 min (0.1–100 ng/ml), and 60 min (100 ng/ml; P<0.05) and caused translocation of p47phox to the membrane similar to lipopolysaccharides. CD11b surface expression was increased by IL-18 in a time- and concentration-dependent manner. IL-18 caused up-regulation of the formyl-Met-Leu-Phe receptor, changes in PMN size, and elastase release. Investigation of signaling demonstrated IL-18-mediated activation of p38 mitogen-activated protein (MAP) kinase in a concentration (0.1–100 ng/ml)-, time (5–15 min)-, and Ca2+-dependent manner. IL-18 directly increased cytosolic Ca2+ concentration. IL-18 activation of PMNs was blocked by inhibition of p38 MAP kinase activity (SB203580) or by inhibition of p38 MAP kinase activation by chelation of cytosolic Ca2+. We conclude that IL-18, at physiologic concentrations, is an effective PMN priming agent that requires p38 MAP kinase activity.
Key Words: inflammation • cytokines • translocation of oxidase components
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