Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes.
The signal transduction pathways regulating smooth-muscle gene expression and production of cytokines in response to proinflammatory mediators are undefined. Cultured human bronchial smooth-muscle cells were treated for 20 h with a cytokine cocktail containing interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma. A complementary DNA expression array containing 588 genes was used to follow cytokine-stimulated gene expression. The expression and secretion of the cytokines IL-1beta, IL-6, and IL-8 significantly increased after 20 h of stimulation as measured by relative reverse transcriptase/ polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting techniques. Expression of IL-6 and IL-8 was sensitive to SB203580, the specific inhibitor of p38 mitogen-activated protein (MAP) kinase and PD98059, an inhibitor of MAP kinase kinase. Expression of IL-1beta was sensitive only to PD98059. Together, these results demonstrate that the p38 and extracellular signal-regulated protein kinase MAP kinase pathways are required for proinflammatory mediator- induced cytokine expression in airway myocytes. The generation of chemokines and cytokines in airway smooth muscle also provides evidence that smooth-muscle cells have the ability to contribute to the inflammatory response.
Hedges
J C
JC
Cell and Molecular Biology Program, Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada, USA.
Singer
C A
CA
Gerthoffer
W T
WT
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one