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Infection-induced kinin B-1 receptors in human pulmonary fibroblasts: Role of intact pathogens and p38 mitogen-activated protein kinase-dependent signaling

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Author

Summary, in English

Kinin B-1 receptors (B1R) are involved in many pathophysiological processes, and its expression is up-regulated in inflammatory pulmonary disease. Although bacteria can generate kinin peptides, the molecular signaling mechanisms regulating B1R during infection by intact pathogens is unknown. The serious opportunistic clinical isolate Burkholderia cenocepacia (B. cen.) belongs to the important B. cepacia complex (Bcc) of gramnegative pathogens that rapidly causes fatal pulmonary disease in hospitalized and immunocompromised patients and those with cystic fibrosis. We demonstrate here that B. cen. infection induced a rapid increase in B1R mRNA (1 h) proceeded by an increase in B1R protein expression (2 h), without affecting B-2 receptor expression in human pulmonary fibroblasts. The B1R response was dose-dependent and maximal by 6 to 8 h (3- to 4- fold increase), however, brief B. cen. infection could sustain B1R up-regulation. In contrast, nonclinical Bcc phytopathogens were much less B1R inducive. The protein synthesis inhibitor cycloheximide and transcriptional inhibitor actinomycin D abrogated the B-1 response to B. cen. indicating de novo B1R synthesis. B. cen. activated p38 mitogen-activated protein kinase ( MAPK), and blocking p38 MAPK with the specific inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB 203580) dramatically reduced B. cen.-induced B1R. Furthermore, B. cen. regulation of B1R was diminished by the anti-inflammatory glucocorticoid dexamethasone. In conclusion, this study is the first demonstration that infection with intact pulmonary pathogens like B. cen. positively modulates the selective expression of B1R. Thus, providing evidence that B1R regulation may be an important and novel mechanism in the inflammatory cascade in response to chronic pulmonary infection and disease.

Department/s

  • Drug Target Discovery

Publishing year

2005

Language

English

Pages

1231-1238

Publication/Series

Journal of Pharmacology and Experimental Therapeutics

Volume

313

Issue

3

Document type

Journal article

Publisher

American Society for Pharmacology and Experimental Therapeutics

Topic

  • Pharmacology and Toxicology

Status

Published

Research group

  • Drug Target Discovery

ISBN/ISSN/Other

  • ISSN: 1521-0103