PubMed2005
Kinin B(1) receptors (B(1)R) 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 B(1)R 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 immunocompromised patients and those with cystic fibrosis. We demonstrate here that B. cen. infection induced a rapid increase in B(1)R mRNA (1 h) proceeded by an increase in B(1)R protein expression (2 h), without affecting B(2) receptor expression in human pulmonary fibroblasts. The B(1)R response was dose-dependent and maximal by 6 to 8 h (3- to 4-fold increase), however, brief B. cen. infection could sustain B(1)R up-regulation. In contrast, nonclinical Bcc phytopathogens were much less B(1)R inducive. The protein synthesis inhibitor cycloheximide and transcriptional inhibitor actinomycin D abrogated the B(1) response to B. cen. indicating de novo B(1)R 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 B(1)R. Furthermore, B. cen. regulation of B(1)R 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 B(1)R. Thus, providing evidence that B(1)R regulation may be an important and novel mechanism in the inflammatory cascade in response to chronic pulmonary infection and disease.