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*
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
Department of Physiology, School of Dentistry, University of Nebraska, Lincoln, NE 68198; and
Amgen, Thousand Oaks, CA 91320
We have examined the role of IL-18 after acute lung inflammation in
rats caused by intrapulmonary deposition of IgG immune complexes.
Constitutive IL-18 mRNA and protein expression (precursor form, 26 kDa)
were found in normal rat lung, whereas in inflamed lungs, IL-18 mRNA
was up-regulated; in bronchoalveolar (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" protein form of IL-18 (18
kDa) appeared in BAL fluids 1–8 h after onset of inflammation. ELISA
studies confirmed induction of IL-18 in inflamed lungs (in lung
homogenates and in BAL fluids). Prominent immunostaining for IL-18 was
found in alveolar macrophages from inflamed lungs. When rat lung
macrophages, fibroblasts, type II cells, and endothelial cells were
cultured in vitro with LPS, only the first two produced IL-18.
Intratracheal administration 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-
, IL-1
, and
cytokine-induced neutrophil chemoattractant, whereas intratracheal
instillation of anti-IL-18 greatly reduced these changes and
prevented increases in BAL content of IFN-
. Intratracheal
administration of the natural antagonist of IL-18, IL-18 binding
protein, resulted in suppressed lung vascular permeability and
decreased BAL content of neutrophils, cytokines, and chemokines. These
findings suggest that endogenous IL-18 functions as a proinflammatory
cytokine in this model of acute lung inflammation, serving as an
autocrine activator to bring about expression of other inflammatory
mediators.
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