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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.
AuthorsCatharina W Wieland, Britta Siegmund, Giorgio Senaldi, Michael L Vasil, Charles A Dinarello, Giamila Fantuzzi
JournalInfection and immunity (Infect Immun) Vol. 70 Issue 3 Pg. 1352-8 (Mar 2002) ISSN: 0019-9567 [Print] United States
PMID11854220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Bacterial Toxins
  • Cytokines
  • DNA-Binding Proteins
  • Exotoxins
  • Interferon Regulatory Factor-1
  • Irf1 protein, mouse
  • Lipopolysaccharides
  • Macrophage Inflammatory Proteins
  • Phosphoproteins
  • Transcription Factors
  • Virulence Factors
  • ADP Ribose Transferases
  • Pseudomonas aeruginosa exotoxin A
  • Type C Phospholipases
Topics
  • ADP Ribose Transferases (pharmacology)
  • Animals
  • Bacterial Toxins (pharmacology)
  • Cytokines (analysis)
  • DNA-Binding Proteins (metabolism)
  • Exotoxins (pharmacology)
  • Female
  • Interferon Regulatory Factor-1
  • Leukocyte Count
  • Leukocytes, Mononuclear (cytology)
  • Lipopolysaccharides (pharmacology)
  • Lung (immunology)
  • Macrophage Inflammatory Proteins (biosynthesis)
  • Male
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration
  • Phosphoproteins (metabolism)
  • Pneumonia (chemically induced, etiology)
  • Pseudomonas aeruginosa (immunology)
  • Transcription Factors (metabolism)
  • Type C Phospholipases (pharmacology)
  • Virulence Factors

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