REGULATION OF LEUKEMIA INHIBITORY FACTOR SYNTHESIS IN CULTURED HUMAN ASTROCYTES

We have examined the ability of human astrocytes to synthesize and sec rete leukemia inhibitory factor (LIF), which is a multifunctional cyto kine that controls cell proliferation and differentiation in many tiss ues, including the nervous system. Astrocyte-enriched cultures, prepar ed from 8- to 9-wk-old embryonic brains, expressed LIF mRNA and secret ed LIF protein. LIF synthesis was significantly increased by the cytok ines IL-1 beta, TNF-alpha, and TGF-beta(1), but not by IFN-gamma, IL-6 , or LPS. No major differences in basal and cytokine-inducible LIF pro duction were detected among astrocyte populations obtained from differ ent brain areas. LIF synthesis was lower in serum-free than in serum-c ontaining astrocyte cultures. A role for protein kinase C in the regul ation of astrocyte LIF production was suggested by the findings that p horbol esters induced both LIF mRNA and protein and that the cytokine- induced LIF increase was partially antagonized by relatively selective inhibitors of protein kinase C such as H7 and staurosporine. Human le ptomeningeal fibroblasts also expressed LIF gene and protein. Astrocyt es produced LIF and responded to cytokines with increased LIF synthesi s only after being subcultured, and not when grown in primary cultures in close contact with neurons. Our findings suggest that in vivo indu ction of astrocyte LIF secretion might occur in pathologic conditions as a consequence of both alterations of neuronal-glial interactions an d a local increase in the level of inflammatory cytokines.