Received for publication January 3, 2005.
Revised February 25, 2005.
Accepted for publication February 28, 2005.

INFECTION-INDUCED KININ B₁ RECEPTORS IN HUMAN PULMONARY FIBROBLASTS: ROLE OF INTACT PATHOGENS AND P38 MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT SIGNALING

Abstract

Kinin B₁ receptors (B₁R) are involved in many pathophysiological processes, and its expression is upregulated 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 gram-negative pathogens that rapidly causes fatal pulmonary disease in hospitalized and immuno-compromised 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 effecting B₂ receptor expression in human pulmonary fibroblasts. The B₁R response was dose-dependent and maximal by 6-8 h (3- to 4-fold increase), however brief B. cen. infection could sustain B₁R upregulation. In contrast, non-clinical Bcc phytopathogens were much less B₁R inducive. The protein synthesis inhibitor cycloheximide and transcriptional inhibitor actinomycin D abrogated the B₁ 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.

Key words: Bradykinin, Burkholderia cepacia, Infection, Inflammation, Pulmonary disease, kinin receptor