title: Bradykinin induces interleukin-6 production in human airway smooth muscle cells: modulation by Th2 cytokines and dexamethasone.
abstract: Synthetic function of airway smooth muscle (ASM), defined as secretion of cytokines or chemokines, may regulate airway inflammatory responses in chronic obstructive lung diseases. Because bradykinin (BK) and interleukin (IL)-6 may play important roles in the regulation of airway inflammation, we tested whether BK induces IL-6 expression from human ASM cells. BK stimulates IL-6 release in a concentration-dependent (0.001-10 micro M) and time-dependent (2-24 h) manner. The increases in IL-6 protein and total mRNA were inhibited by the selective B(2) receptor antagonist HOE-140 but not by the selective B(1) receptor antagonist desArg(9)(Leu(8))-BK. Actinomycin D (a transcription inhibitor), dexamethasone, indomethacin, IL-4, and IL-13 (Th(2) type cytokines) inhibited the expression of IL-6 by BK. In contrast, BK-induced IL-6 secretion was enhanced by exogenous prostaglandin E(2) and salmeterol. Using immunoblot analysis, we showed that BK activates ERK1/2 and p38 mitogen-activated protein kinases (MAPK). Blocking ERK1/2 with PD98059 or p38 MAPK with SB203580 reduced BK-induced IL-6 expression. BK also activates luciferase activity in ASM cells transfected with a reporter plasmid containing AP-1 enhancer elements. BK-induced, AP-1-dependent transcription was inhibited by indomethacin and dexamethasone. Curcumin, an inhibitor of AP-1, also reduced BK-induced IL-6 expression. These data show that BK, via the B(2) receptor, induces IL-6 expression in ASM cells by involving ERK1/2 and p38 MAPK signaling pathways and the AP-1 transcription factor. Moreover, IL-6 secretion by BK is sensitive to corticosteroids and is regulated by Th(2)-derived cytokines.
authors.affiliation: Department of Thoracic Medicine II, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Chien-Da
authors.initials: CD
authors.lastname: Huang
authors.forename: Omar
authors.initials: O
authors.lastname: Tliba
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Yassine
authors.initials: Y
authors.lastname: Amrani
mesh_terms: D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D007700:Kinetics; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018002:Receptors, Bradykinin / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D016207:Cytokines; D018793:Interleukin-13; D015850:Interleukin-6; D012333:RNA, Messenger; D018002:Receptors, Bradykinin; D015847:Interleukin-4; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000420:Albuterol; D001920:Bradykinin