Stimulation of stress-activated but not mitogen-activated protein kinases by tumour necrosis factor receptor subtypes in airway smooth muscle

The multifunctional cytokine tumour necrosis factor-alpha (TNF) displays ma ny physiological effects in a variety of tissues, especially proliferative and cytotoxic actions in immunological cells. Recently, we uncovered an imp ortant new mechanism by which TNF can sensitise airway smooth muscle (ASM) to a fixed intracellular Ca2+ concentration which in vivo would produce a m arked hypercontractility of the airways. Here, we report that both 50-60 kD a type I TNFR (TNFR1) and 70-80 kDa type II TNFR (TNFR2) receptor subtypes were expressed in ASM cells and selectively activated the stress kinases, c -Jun N-terminal kinase and p38 mitogen-activated protein kinase (p38 MAPK), However, TNF caused no activation of p42/p44 MAPK or cytosolic phospholipa se A(2) activity. In contrast, TNF stimulation of the TNFR1, but not the TN FR2, elicited nuclear factor-kappaB transcription factor function, a specie s known to be important in mediation of certain inflammatory cellular respo nses. This is the first report of TNF receptor subtypes in ASM cells causin g selective kinase activation, which may prove important in therapeutic str ategies for treating immune airway disorders such as chronic obstructive pu lmonary disease and asthma. (C) 2001 Elsevier Science Inc. All rights reser ved.