Leukotriene B4 mediates histamine induction of NF-kappaB and IL-8 in human bronchial epithelial cells.
In 16HBE transformed human bronchial epithelial cells, histamine stimulated interleukin (IL)-8 mRNA and protein secretion, and this histamine stimulation was inhibited by the H1-receptor antagonist diphenhydramine (DPH), by the inhibitor of 5-lipoxygenase-activating protein (FLAP) MK-886, by the 5-lipoxygenase inhibitor Zileuton, and by dexamethasone. Histamine stimulated bronchial epithelial cell production of leukotriene B4 (LTB4), and this production was inhibited by FLAP inhibitors MK-886 and L-655,238 and Zileuton. Histamine stimulated IL-8 luciferase reporter gene activity that was inhibited with DPH, dexamethasone, MK-886 and L-655,238, and Zileuton. The inhibition of IL-8 transcription and protein secretion by FLAP inhibitors and Zileuton was reversed with exogenous LTB4. There was increased IL-8 nuclear factor-kappaB (NF-kappaB) DNA-binding activity after histamine stimulation, and this was inhibited by DPH and MK-886. Cytoplasmic phospholipase A2 mRNA levels were also potently induced by histamine. Thus histamine stimulation of bronchial epithelial cells involves binding at H1 receptors, production of LTB4, activation of NF-kappaB and increased expression of IL-8.
Aoki
Y
Y
Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Qiu
D
D
Zhao
G H
GH
Kao
P N
PN
D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D007975:Leukotriene B4 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D016328:NF-kappa B / Q000096:biosynthesis* / Q000378:metabolism; D010741:Phospholipases A / Q000235:genetics; D054467:Phospholipases A2; D016133:Polymerase Chain Reaction; D011804:Quinolines; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D002722:Chlorobenzenes
D006632:Histamine; D006918:Hydroxyurea; D007211:Indoles; D016209:Interleukin-8; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D010741:Phospholipases A; D054467:Phospholipases A2; D011804:Quinolines; D012333:RNA, Messenger; C095607:L 655238; C060893:MK-886; D002722:Chlorobenzenes; C063449:zileuton