DUAL CONTROL OF NEURITE OUTGROWTH BY STAT3 AND MAP KINASE IN PC12 CELLS STIMULATED WITH INTERLEUKIN-6

IL-6 induces differentiation of PC12 cells pretreated with nerve growt h factor (NGF), We explored the signals required for neurite outgrowth of PC12 cells by using a series of mutants of a chimeric receptor con sisting of the extracellular domain of the granulocyte-colony stimulat ing factor (G-CSF) receptor and the cytoplasmic domain of gp130, a sig nal-transducing subunit of the IL-6 receptor, The mutants incapable of activating the MAP kinase cascade failed to induce neurite outgrowth, Consistently, a MEK inhibitor, PD98059, inhibited neurite outgrowth, showing that activation of the MAP kinase cascade is essential for the differentiation of PC12 cells, In contrast, a mutation that abolished the ability to activate STAT3 did not inhibit, but rather stimulated neurite outgrowth, This mutant did not require NGF pretreatment for ne urite outgrowth, Dominant-negative STAT3s mimicked NGF pretreatment, a nd NGF suppressed the IL-6-induced activation of STAT3, supporting the idea that STAT3 might regulate the differentiation of PC12 cells nega tively, These results suggest that neurite outgrowth of PC12 cells is regulated by the balance of MAP kinase and STAT3 signal transduction p athways, and that STAT3 activity can be regulated negatively by NGF.