MICROTUBULE INTEGRITY REGULATES SRC-LIKE AND EXTRACELLULAR SIGNAL-REGULATED KINASE-ACTIVITIES IN HUMAN PRO-MONOCYTIC CELLS - IMPORTANCE FORINTERLEUKIN-1 PRODUCTION

We have demonstrated previously that microtubule depolymerization by c olchicine in human monocytes induces selective production of interleuk in-1 (IL-1) (Manie, S., Schmid-Alliana, A., Kubar, J., Ferrua, B., and Rossi, B. (1993) J. Biol. Chem. 268, 13675-13681), Here, we provide e vidence that disruption of the microtubule structure rapidly triggers extracellular signal-regulated kinase (ERK) activation, whereas it was without effect on SAPK2 activity, which is commonly acknowledged to c ontrol pro-inflammatory cytokine production, This process involves the activation of the entire cascade including Ras, Raf-1, MEK1/2, ERK1, and ERK2, Activation of ERKs is followed by their nuclear translocatio n, Although other SAPK congeners might be activated upon microtubule d epolymerization, the activation of ERK1 and ERK2 is mandatory for IL-1 production as shown by the blocking effect of PD 98059, a specific ME K1/2 inhibitor, Additionally, we provide evidence that microtubule dis ruption also induces the activation of c-Src and Hck activities, The i mportance of Src kinases in the mediation of the colchicine effect is underscored by the fact that CP 118556, a specific inhibitor of Src li ke kinase, abrogates both the colchicine-induced ERK activation and IL -1 production. This is the first evidence that ERK activation is an ab solute prerequisite for induction of this cytokine, Altogether, our da ta lend support to a model where the status of microtubule integrity c ontrols the level of Src activities that subsequently activate the ERK kinase cascade, thus leading to IL-1 production.