Tumor necrosis factor receptor (TNFR) 1, but not TNFR2, mediates tumor necrosis factor-alpha-induced interleukin-6 and RANTES in human airway smooth muscle cells: Role of p38 and p42/44 mitogen-activated protein kinases

Little information is available regarding the mechanisms involved in cytoki ne-induced synthetic function of human airway smooth muscle (ASM) cells. He re, we report that tumor necrosis factor receptor (TNFR) 1-induced p38 and p42/44 mitogen-activated protein kinase (MAPK) activation modulates tumor n ecrosis factor-alpha (TNF alpha)-mediated synthetic responses: expression o f intercellular adhesion molecule-1 (ICAM-1) and secretion of interleukin ( IL)-6 and the regulated-on-activation, normal T-cell expressed and secreted (RANTES) chemokine in human ASM cells. Pretreatment of ASM cells with SB20 3580, a p38 MAPK inhibitor, slightly enhanced TNF alpha -induced ICAM-1 exp ression in a dose-dependent manner but partially inhibited secretion of RAN TES and IL-6. In contrast, PD98059, a p42/44 inhibitor, reduced ICAM-1 expr ession by 50% but had no effect on TNF alpha -induced RANTES or IL-6 secret ion. SB203580 and PD98059 had little effect on TNF alpha -induced nuclear f actor-kappaB (NF-kappaB) activation as determined in cells transfected with a NF-kappaB-luciferase reporter construct. We also found that agonistic an tibodies specific for either TNFR1 or TNFR2 stimulated IL-6 and RANTES secr etion and activated p38 and p42/44 MAPKs. In addition, both antibodies indu ced NF-kappaB-mediated gene transcription. Using receptor-specific blocking antibodies, we found that TNFR1 primarily regulates TNF alpha -induced IL- 6 and RANTES secretion and activation of p38 and p42/44 MAPK pathways. Inte restingly, we found that TNFR1 and TNFR2 are expressed differently on the c ell surface of ASM cells. Our data suggest that despite the presence of fun ctional TNFR2, TNFR1 associated with MAPK-dependent and -independent pathwa ys is the primary signaling pathway involved in TNF alpha -induced syntheti c functions in ASM cells.