Am. J. Respir. Crit. Care Med., Volume 164, Number 4, August 2001, 688-697

Inhibitors of Mitogen-activated Protein Kinases Differentially Regulate Eosinophil-activating Cytokine Release from Human Airway Smooth Muscle

MATTHEW P. HALLSWORTH, LYN M. MOIR, DILYS LAI, and STUART J. HIRST

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

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)-1-stimulated GM-CSF, RANTES, and eotaxin release. IL-1 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-1-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.

Keywords: airway smooth muscle; chemokines; mitogen-activated protein kinases; asthma.

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