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 proinflammator y cytokines during airway inflammation. In the present study, we examined a requirement for mitogen-activated protein (MAP) kinase activation for inte rleukin (IL)-1 beta -stimulated GM-CSF, RANTES, and eotaxin release. IL-1 b eta induced concentration-dependent phosphorylation of p42/p44 extracellula r signal-regulated kinases (ERKs), p38 MAP kinase, and c-Jun amino-terminal kinase (SAPK/JNK). p42/p44 ERK and p38 MAP kinase phosphorylation peaked a t 15 min and remained elevated up to 4 h. SAPK/JNK phosphorylation also pea ked at 15 min but fell to baseline within 60 min. SB 203580 selectively inh ibited IL-1 beta -stimulated activation of p38 MAP kinase; U 0126 was selec tive against p42/p44 ERK activity. SB 202474, an inactive analog, had no ef fect 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, w hereas RANTES release was prevented by U 0126 only. GM-CSF release was inhi bited 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/p4 4 ERK dependent and is tonically suppressed by a mechanism that is partiall y dependent on p38 MAP kinase, though direct inhibition of cyclooxygenase ( COX) activity due to poor inhibitor selectivity may also contribute.