title: Bradykinin-stimulated p42/p44 MAPK activation associated with cell proliferation in corneal keratocytes.
abstract: Bradykinin (BK) is released into the tear-film in ocular allergic patients. BK has been shown to exert mitogenic effects on several cell types. However, the mechanisms underlying its action on corneal keratocytes (CKs) were largely unknown. This study was to investigate the mitogenic effect of BK on rabbit CKs linked to activation of p42/p44 mitogen-activated protein kinase (MAPK), assessed by [3H]thymidine incorporation and Western blotting analysis, respectively. BK stimulated [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in a time- and concentration-dependent manner. Pretreatment with pertussis toxin attenuated the BK-induced responses. BK-stimulated responses were attenuated by inhibitors of selective B2 receptor (Hoe 140), phosphatidylinositol (PI)-PLC (U73122), an intracellular Ca2+chelator (BAPTA/AM), PKC (GF109203X), tyrosine kinase (genistein), and MEK1/2 (PD98059). BK also stimulated translocation of p42/p44 MAPK into nucleus and led to expression of c-fos and c-jun in CKs. These results demonstrate that in CKs, BK-stimulated phosphorylation of p42/p44 MAPK is mediated through the activation of BK B2 receptors and leads to cell proliferation.
authors.affiliation: Department of Physiology and Pharmacology, College of Medicine, Chang Gung University 259 Wen-Hwa 1 Road, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Cheng
authors.forename: Samuel C M
authors.initials: SC
authors.lastname: Huang
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
authors.forename: Chi-Chin
authors.initials: CC
authors.lastname: Sun
authors.forename: Mei-Jie
authors.initials: MJ
authors.lastname: Jou
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011817:Rabbits; D043782:Receptor, Bradykinin B2 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D043782:Receptor, Bradykinin B2; D037342:Pertussis Toxin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D001920:Bradykinin