title: Pulmonary inflammation induced by Pseudomonas aeruginosa lipopolysaccharide, phospholipase C, and exotoxin A: role of interferon regulatory factor 1.
abstract: Chronic pulmonary infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) patients. P. aeruginosa lipopolysaccharide (LPS), phosholipase C (PLC), and exotoxin A (ETA) were evaluated for their ability to induce pulmonary inflammation in mice following intranasal inoculation. Both LPS and PLC induced high levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta-6, gamma interferon (IFN-gamma), MIP-1 alpha MIP-2 in the lungs but did not affect IL-18 levels. ETA did not induce TNF-alpha and was a weak inducer of IL-1 beta, IL-6, macrophage inflammatory protein 1 alpha (MIP-1 alpha), and MIP-2. Remarkably, ETA reduced constitutive lung IL-18 levels. LPS was the only factor inducing IFN-gamma. LPS, PLC, and ETA all induced cell infiltration in the lungs. The role of interferon regulatory factor-1 (IRF-1) in pulmonary inflammation induced by LPS, PLC, and ETA was evaluated. When inoculated with LPS, IRF-1 gene knockout (IRF-1 KO) mice produced lower levels of TNF-alpha, IL-1 beta, and IFN-gamma than did wild-type (WT) mice. Similarly, a milder effect of ETA on IL-1 beta and IL-18 was observed for IRF-1 KO than for WT mice. In contrast, the cytokine response to PLC did not differ between WT and IRF-1 KO mice. Accordingly, LPS and ETA, but not PLC, induced expression of IRF-1 mRNA. IRF-1 deficiency had no effect on MIP-1 alpha and MIP-2 levels and on cell infiltration induced by LPS, PLC, or ETA. Flow cytometric evaluation of lung mononuclear cells revealed strongly reduced percentages of CD8(+) and NK cells in IRF-1 KO mice compared to percentages observed for WT mice. These data indicate that different virulence factors from P. aeruginosa induce pulmonary inflammation in vivo and that IRF-1 is involved in some of the cytokine responses to LPS and ETA.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Catharina W
authors.initials: CW
authors.lastname: Wieland
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.forename: Giorgio
authors.initials: G
authors.lastname: Senaldi
authors.forename: Michael L
authors.initials: ML
authors.lastname: Vasil
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Giamila
authors.initials: G
authors.lastname: Fantuzzi
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005098:Exotoxins / Q000494:pharmacology; D005260:Female; D050856:Interferon Regulatory Factor-1; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D010750:Phosphoproteins / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced / Q000209:etiology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*; D010738:Type C Phospholipases / Q000494:pharmacology; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D016207:Cytokines; D004268:DNA-Binding Proteins; D005098:Exotoxins; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D010738:Type C Phospholipases; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C494258:Irf1 protein, mouse