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INFLAMMATION AND IMMUNOPHARMACOLOGY

Infection-Induced Kinin B₁ Receptors in Human Pulmonary Fibroblasts: Role of Intact Pathogens and p38 Mitogen-Activated Protein Kinase-Dependent Signaling

Developmental Biology Program, Saban Research Institute, Childrens Hospital Los Angeles, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California (S.B.P., K.R., B.J.S., D.W.); and Department of Physiological Sciences, Lund University, Lund, Sweden (L.M.F.L.-L.)

Kinin B₁ 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 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 B₁R mRNA (1 h) proceeded by an increase in B₁R protein expression (2 h), without affecting B₂ 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 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.

Address correspondence to: Dr. Stephen B. Phagoo, Developmental Biology Program, Saban Research Institute, Childrens Hospital Los Angeles, Department of Surgery, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard, MS #35, SABAN RM 507, Los Angeles, CA 90027. E-mail: sphagoo{at}chla.usc.edu