TUMOR-NECROSIS-FACTOR-ALPHA INDUCES INTERLEUKIN-6 PRODUCTION AND INTEGRIN LIGAND EXPRESSION BY DISTINCT TRANSDUCTION PATHWAYS

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that elicits a large number of biological effects. However, the intracellu lar signaling mechanisms that are responsible for the TNF-alpha effect s remain largely unknown. We have previously demonstrated that culture d mouse Sertoli cells, after TNF-alpha treatment, increase the surface expression of adhesion molecules such as intercellular adhesion molec ule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and inte rleukin-6 (IL-6) production (Riccioli, A., Filippini, A., De Cesaris, P., Barbacci, E., Stefanini, M., Starace, G., and Ziparo, E. (1995) Pr oc. Natl. Acad Sci. U.S.A. 92, 5808-5812). Here, we show that, in cult ured Sertoli cells, TNF-alpha activates the mitogen-activated protein kinase pathway (p38, c-Jun N-terminal protein kinase/stress-activated protein kinase, and the p42/p44 mitogen-activated protein kinases) as revealed by an increased phosphorylation of p38, activating transcript ion factor-2, c-Jun, and Elk-1. Furthermore, our data indicate that th e biological effects induced by TNF-alpha in Sertoli cells (enhancemen t of ICAM-1, VCAM-1, and IL-6 expression) depend on the activation of different signaling pathways. SB203580, a highly specific p38 inhibito r, does not affect ICAM-1 and VCAM-1 expression, but strongly inhibits IL-6 production. Moreover, interferon-gamma, which up-regulates adhes ion molecule expression and reduces IL-6 production, does not induce p hosphorylation of p38. Our data strongly support the hypothesis that, in response to TNF-alpha, activation of p38 leads to IL-6 production, whereas ICAM-1 and VCAM-1 expression could be induced by activation of the c-Jun N-terminal protein kinase/stress activated protein kinase p athway.