Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle.
Airway smooth muscle (ASM) is a potential source of multiple proinflammatory cytokines during airway inflammation. In the present study, we examined a requirement for mitogen-activated protein (MAP) kinase activation for interleukin (IL)-1beta-stimulated GM-CSF, RANTES, and eotaxin release. IL-1beta induced concentration-dependent phosphorylation of p42/p44 extracellular signal-regulated kinases (ERKs), p38 MAP kinase, and c-Jun amino-terminal kinase (SAPK/JNK). p42/p44 ERK and p38 MAP kinase phosphorylation peaked at 15 min and remained elevated up to 4 h. SAPK/JNK phosphorylation also peaked at 15 min but fell to baseline within 60 min. SB 203580 selectively inhibited IL-1beta-stimulated activation of p38 MAP kinase; U 0126 was selective against p42/p44 ERK activity. SB 202474, an inactive analog, had no effect on p42/p44 ERK, p38 MAP kinase, or SAPK/JNK activation, or on eotaxin or RANTES release. Eotaxin release was inhibited by SB 203580 and U 0126, whereas RANTES release was prevented by U 0126 only. GM-CSF release was inhibited by U 0126 but enhanced by SB 203580. These data indicate that RANTES release is dependent on p42/p44 ERK activation but occurs independently of p38 MAP kinase activity. Eotaxin release, however, is dependent on both p38 MAP kinase- and p42/p44 ERK-dependent mechanisms. GM-CSF release is p42/p44 ERK dependent and is tonically suppressed by a mechanism that is partially dependent on p38 MAP kinase, though direct inhibition of cyclooxygenase (COX) activity due to poor inhibitor selectivity may also contribute.
Hallsworth
M P
MP
Department of Respiratory Medicine and Allergy, The Guy's, King's and St. Thomas' School of Medicine, King's College London, Thomas Guy House, Guy's Hospital Campus, London, United Kingdom.
Moir
L M
LM
Lai
D
D
Hirst
S J
SJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology*; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D002070:Butadienes / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000032:analysis / Q000187:drug effects* / Q000276:immunology*; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology*; D005260:Female; D005419:Flavonoids / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D008173:Lung Diseases, Obstructive / Q000188:drug therapy* / Q000276:immunology*; D048728:MAP Kinase Kinase Kinase 1; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D009570:Nitriles / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis* / Q000276:immunology*; D011725:Pyridines / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects* / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002070:Butadienes; D016207:Cytokines; D005419:Flavonoids; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; C113580:U 0126; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one