The levels of leukemia inhibitory factor mRNA in a Schwann cell line are regulated by multiple second messenger pathways

Axotomy of sympathetic and sensory neurons leads to changes in their neurop eptide phenotypes, These changes are mediated in part by the induction of l eukemia inhibitory factor (LIF) by nonneuronal cells. In the present study, we identified satellite/Schwann cells as a possible source of the injury-i nduced LIF. Using a Schwann cell line, SC-1 cells, we examined mechanisms o f LIF induction. LIF mRNA levels increased rapidly when the cells were trea ted with 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate, phorbo l 12-myristate 13-acetate (PMA), or A23187. Among these reagents, PMA was t he most efficacious. Inhibition of protein kinase C (PKC) by GF-109203X sig nificantly reduced the PMA-induced LIF mRNA levels. As PKC is known to acti vate the extracellular signal-regulated kinase (ERK) signaling pathway, the involvement of this pathway in the PMA-stimulated induction of LIF mRNA wa s examined. Phosphorylation of ERKs was increased following PMA treatment i n SC-I cells. Moreover, inhibition of ERK kinase activity by PD98059 dramat ically reduced PMA-stimulated phosphorylation of ERKs and induction of LIF mRNA. These results indicate that LIF mRNA levels can be regulated by ERK a ctivation via stimulation of PKC in Schwann cells.