Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3

Signals of interleukin 6 (IL-6) are transduced by binding of IL-6 to its ce ll surface receptor (IL-6R) and subsequent association of the resultant IL- 6/IL-6R complex with gp130, the signal transducing receptor component utili zed in common by all the IL-6 family of cytokines, A soluble form of IL-6R (sIL-6R), which lacks transmembrane and cytoplasmic regions, retains the ab ility to bind IL-6 and signal through gp130, We show here that a fusion pro tein of sIL-6R and IL-6 without a polypeptide linker, termed FP6, induces d ifferentiation of astrocytes from fetal mouse neuroepithelial cells as pote ntly as a representative IL-6 family cytokine, leukaemia inhibitory factor (LIF). FP6 has a potential to activate a transcription factor, signal trans ducer and activator of transcription 3 (STAT3), and mitogen-activated prote in kinases, ERK1 and ERK2, in these cells as does LIF, FP6 activates a prom oter of the gene for an astrocytic marker, glial fibrillary acidic protein (GFAP), in neuroepithelial cells. This activation is virtually abolished by ectopic expression of a dominant-negative form of STAT3, or by introducing a point mutation into the STAT3 response element located in the GFAP promo ter. These results suggest that FP6 induces astrocyte differentiation from neuroepithelial cells through STAT3 activation and that FP6 could be of use as a substitute for natural IL-6 family cytokines, (C) 2001 Academic Press .