title: Role of c-jun N-terminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells.
abstract: 1. Human airway smooth muscle cells (HASMC) contribute to airway inflammation in asthma by virtue of their capacity to produce several inflammatory mediators including IL-8, GM-CSF and RANTES. The intracellular signal pathway underlying the production of these cytokines in HASMC is not entirely elucidated. 2. We examined the role of the mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK) in TNFalpha- and IL-1beta-induced GM-CSF, RANTES and IL-8 production in HASMC by using a novel specific inhibitor for JNK (SP600125). 3. Confluent HASMC were treated with TNFalpha or IL-1beta (10 ng ml(-1)) for 24 h in the presence or absence of SP600125 (1-100 micro M). JNK activity was determined by a kinase assay. Phosphorylation of JNK, p38 MAPK and ERK was examined by Western blotting. Culture supernatants were assayed for GM-CSF, RANTES and IL-8 content by ELISA. 4. Maximum TNFalpha- or IL-1beta-induced phosphorylation of JNK in HASMC occurred after 15 min and returned to baseline levels after 4 h. SP600125 inhibited TNFalpha- and IL-1beta-induced JNK activity in HASMC as shown by the reduced phosphorylation of its substrate c-jun. Furthermore, GM-CSF, RANTES and to a lesser extent IL-8 release from HASMC treated with TNFalpha and IL-1beta was inhibited dosedependently by SP600125. 5. JNK activation is involved in TNFalpha- and IL-1beta-induced GM-CSF, RANTES and IL-8 production from HASMC. JNK may therefore represent a critical pathway for cytokine production in HASMC.
authors.affiliation: Thoracic Medicine, National Heart & Lung Institute, Imperial College, Dovehouse St, London SW3 6LY, UK.
authors.forename: Ute
authors.initials: U
authors.lastname: Oltmanns
authors.forename: Razao
authors.initials: R
authors.lastname: Issa
authors.forename: Maria B
authors.initials: MB
authors.lastname: Sukkar
authors.forename: Matthias
authors.initials: M
authors.lastname: John
authors.forename: K Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases