Bradykinin induces interleukin-6 production in human airway smooth muscle cells: modulation by Th2 cytokines and dexamethasone.
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.
Huang
Chien-Da
CD
Department of Thoracic Medicine II, Chang Gung Memorial Hospital, Taipei, Taiwan.
Tliba
Omar
O
Panettieri
Reynold A
RA
Amrani
Yassine
Y
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
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