Activation of gp 130 by IL-6/soluble IL-6 receptor induces neuronal differentiation

Interleukin‐6 (IL‐6) on target cells binds to the specific IL‐6 receptor (IL‐6R) and subsequently induces homodimerization of the signal‐transducing protein gpl30. Cells which express gpl30 but no IL‐6R and which therefore do not respond to IL‐6 can be stimulated by the complex of IL‐6 and soluble IL‐6R (slL‐6R). Here we show that on rat pheochromocytoma cells (PC12), the combination of IL‐6 and slL‐6R but not IL‐6 alone induces expression of c‐fos, GAP‐43 and neuron‐specific enolase followed by neuron‐specific differentiation and formation of a neuronal network. The differentiation was dose‐and time‐dependent and followed the same kinetics as nerve‐growth factor (NGF)‐induced differentiation. The responses of PC12 cells to IL‐6/slL‐6R and NGF were additive, suggesting independent signaling pathways. We demonstrate that activation of gpl30 generates a neuronal differentiation signal that is equivalent to and independent of trk/NGF receptor tyrosine kinase. Interestingly, the failure of IL‐6 to induce differentiation of PC12 cells is not due to lack of surface expression of IL‐6R as IL‐6 alone triggered expression of GAP‐43 mRNA and protein. We hypothesize that PC12 cells express more gp130 than IL‐6R and that the extent of activated gp130 molecules determines the quality of the response.