Activation of gp130 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 gp130. Cells which express gp130 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/sIL-6R and NGF were additive, suggesting independent signaling pathways. We demonstrate that activation of gp130 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.
März
P
P
I.Department of Medicine, Mainz University, Germany.
Herget
T
T
Lang
E
E
Otten
U
U
Rose-John
S
S
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D001667:Binding, Competitive / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D050822:Cytokine Receptor gp130; D019922:GAP-43 Protein / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology; D016501:Neurites / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000648:ultrastructure; D009500:Neutralization Tests; D016716:PC12 Cells; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility
D000906:Antibodies; D015703:Antigens, CD; D019922:GAP-43 Protein; C494199:IL6ST protein, human; C494201:Il6st protein, rat; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D016760:Proto-Oncogene Proteins c-fos; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130