Role of IL-18 in acute lung inflammation

We have examined the role of IL-18 after acute lung inflammation in rats ca used by intrapulmonary deposition of IgG immune complexes. Constitutive IL- 18 mRNA and protein expression (precursor form, 26 kDa) were found in norma l rat lung, whereas in inflamed lungs, IL-18 mRNA was up-regulated; in bron choalveolar (BAL) fluids, the 26-kDa protein form of IL-18 was increased at 2-4 h in inflamed lungs and remained elevated at 24 h, and the "mature" pr otein form of IL-18 (18 kDa) appeared in BAL fluids 1-8 h after onset of in flammation. ELISA studies confirmed induction of IL-18 in inflamed lungs (i n lung homogenates and in BAL fluids). Prominent immunostaining for IL-18 w as found in alveolar macrophages from inflamed lungs. When rat lung macroph ages, fibroblasts, type II cells, and endothelial cells were cultured in vi tro with LPS, only the first two produced IL-18. Intratracheal administrati on of rat recombinant IL-18 in the lung model caused significant increases in lung vascular permeability and in BAL content of neutrophils and in BAL content of TNF-alpha, IL-1 beta, and cytokine-induced neutrophil chemoattra ctant, whereas intratracheal instillation of anti-IL-18 greatly reduced the se changes and prevented increases in BAL content of IFN-gamma. Intratrache al administration of the natural antagonist of IL-18, IL-18 binding protein , resulted in suppressed lung vascular permeability and decreased BAL conte nt of neutrophils, cytokines, and chemokines. These findings suggest that e ndogenous IL-18 functions as a proinflammatory cytokine in this model of ac ute lung inflammation, serving as an autocrine activator to bring about exp ression of other inflammatory mediators.