Interleukin-9 (IL-9) induces cell growth arrest associated with sustained signal transducer and activator of transcription activation in lymphoma cells overexpressing the IL-9 receptor.
Murine interleukin (IL)-9 inhibits apoptosis in murine T lymphomas via signal transducer and activator of transcription (STAT) factors. After transfection of the human IL-9 receptor, human IL-9 had a similar antiapoptotic activity, but, unlike the mouse protein, inhibited proliferation. This effect was correlated with the level of receptor expression and the extent of STAT phosphorylation. Expression of a moderate level of suppressor of cytokine signaling 3 (SOCS3) reduced STAT activation by human IL-9 and prevented inhibition of growth but not of apoptosis. Using mutated IL-9 receptors, we showed that inhibition of proliferation was correlated with STAT1 and STAT3 activation by IL-9 and induction of the cell cycle inhibitor p19/ink4d, a STAT3 target gene. Activation of STAT1 by IFN-gamma did not result in cell growth arrest. In this model, cell growth inhibition is therefore associated with a higher number of receptors, a more robust STAT activation, and a greater sensitivity to SOCS3 expression, compared to apoptosis inhibition.
Demoulin
J B
JB
Ludwig Institute for Cancer Research and the Experimental Medicine Unit of the Université de Louvain, Brussels, Belgium.
Van Snick
J
J
Renauld
J C
JC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D016906:Interleukin-9 / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008894:Milk Proteins; D018123:Receptors, Interleukin / Q000187:drug effects* / Q000378:metabolism; D053651:Receptors, Interleukin-9; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D002352:Carrier Proteins; C493975:Cdkn2d protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D004268:DNA-Binding Proteins; C508045:IL9R protein, human; D016906:Interleukin-9; D008894:Milk Proteins; D018123:Receptors, Interleukin; D053651:Receptors, Interleukin-9; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators