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Infection and Immunity, March 2002, p. 1352-1358, Vol. 70, No. 3
0019-9567/02/$04.00+0 DOI: 10.1128/IAI.70.3.1352-1358.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
Pulmonary Inflammation Induced by Pseudomonas aeruginosa Lipopolysaccharide, Phospholipase C, and Exotoxin A: Role of Interferon Regulatory Factor 1
Catharina W. Wieland,1 Britta Siegmund,1 Giorgio Senaldi,2 Michael L. Vasil,3 Charles A. Dinarello,1 and Giamila Fantuzzi1*
Department of Medicine,1
Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado ,3
Amgen Inc., Thousand Oaks, California2
Received 6 September 2001/
Accepted 20 December 2001
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-
), interleukin 1ß (IL-1ß), IL-6, gamma interferon (IFN-
), MIP-1
and MIP-2 in the lungs but did not affect IL-18 levels. ETA did not induce TNF-
and was a weak inducer of IL-1ß, IL-6, macrophage inflammatory protein 1
(MIP-1
), and MIP-2. Remarkably, ETA reduced constitutive lung IL-18 levels. LPS was the only factor inducing IFN-
. 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-
, IL-1ß, and IFN-
than did wild-type (WT) mice. Similarly, a milder effect of ETA on IL-1ß 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
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.
* Corresponding author. Mailing address: Division of Infectious Diseases B168, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262. Phone: (303) 315-0053. Fax: (303) 315-8054. E-mail:
Giamila.Fantuzzi{at}UCHSC.edu.
Infection and Immunity, March 2002, p. 1352-1358, Vol. 70, No. 3
0019-9567/02/$04.00+0 DOI: 10.1128/IAI.70.3.1352-1358.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
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