TUMOR-NECROSIS-FACTOR-ALPHA STIMULATES AP-1 ACTIVITY THROUGH PROLONGED ACTIVATION OF THE C-JUN KINASE

Tumor necrosis factor alpha (TNF alpha) has multiple biological functi ons including the prolonged activation of the collagenase and c-jun ge nes, which are regulated via their AP-1 binding sites. We show that in cubating human fibroblasts with TNF alpha induces prolonged activation of JNK, the c-Jun kinase, which phosphorylates the transactivation do main of c-Jun. Furthermore, an immune complex kinase assay specificall y demonstrates that TNF alpha stimulates the activity of JNK1, the rec ently described predominant form of JNK. TNF alpha also produces a sma ll and transient increase in extracellular signal-regulated kinase (ER K) activity and no measured increase in Raf-1 kinase activity. On the other hand, epidermal growth factor causes a prolonged activation of R af-1 kinase and ERK activity and a smaller, more transient activation of JNK, whereas the phorbol ester phorbol 12-myristate 13-acetate caus es a small stimulation of Raf-1 kinase and a pronounced stimulation of ERK activity. The activation of JNK by TNF alpha does not correlate w ith Raf-1 or ERK activity. The kinetics of Raf-1, ERK, and JNK inducti on by epidermal growth factor, phorbol 12-myristate 13-acetate, or TNF alpha indicate distinct mechanisms of activation in human fibroblasts .