Role of IL-18 in acute lung inflammation.
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-alpha, IL-1beta, and cytokine-induced neutrophil chemoattractant, whereas intratracheal instillation of anti-IL-18 greatly reduced these changes and prevented increases in BAL content of IFN-gamma. 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.
Jordan
J A
JA
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Guo
R F
RF
Yun
E C
EC
Sarma
V
V
Warner
R L
RL
Crouch
L D
LD
Senaldi
G
G
Ulich
T R
TR
Ward
P A
PA
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006023:Glycoproteins / Q000494:pharmacology; D007105:Immune Complex Diseases / Q000097:blood / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D007249:Inflammation / Q000097:blood / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000276:immunology; D008171:Lung Diseases / Q000097:blood / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020332:Rats, Inbred LEC
D000906:Antibodies; D016207:Cytokines; D006023:Glycoproteins; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; C118370:interleukin-18 binding protein