Role of c-jun N-terminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells

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Journal Article
British Journal of Pharmacology, 2003, 139 (6), pp. 1228 - 1234
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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 TNFα- and IL-1β-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 TNFα or IL-1β (10 ng ml -1) for 24 h in the presence or absence of SP600125 (1-100 μM). 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 TNFα- or IL-1β-induced phosphorylation of JNK in HASMC occurred after 15 min and returned to baseline levels after 4 h. SP600125 inhibited TNFα- and IL-1β-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 TNFα and IL-1β was inhibited dosedependently by SP600125. 5. JNK activation is involved in TNFα- and IL-1β-induced GM-CSF, RANTES and IL-8 production from HASMC. JNK may therefore represent a critical pathway for cytokine production in HASMC.
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