IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells.
IFN-alpha consists of a family of highly homologous proteins, which exert pleiotropic effects on a wide variety of cell types. The biologic activities of IFN-alpha are mediated by its binding to a multicomponent receptor complex resulting in the activation of the Janus kinase-STAT signaling pathway. In most cell types, activation of Stat1 and Stat2 by IFN-alpha leads to the formation of either STAT homo-/heterodimers or of the IFN-stimulated gene factor 3 complex composed of Stat1, Stat2, and p48, a non-STAT protein. These distinct transcriptional complexes then target two different sets of cis-elements, gamma-activated sites and IFN-stimulated response elements. Here, we report that IFN-alpha can activate complexes containing Stat6, which, until now, has been primarily associated with signaling by two cytokines with biologic overlap, IL-4 and IL-13. Induction of Stat6 complexes by IFN-alpha appears to be cell type specific, given that tyrosine phosphorylation of Stat6 in response to IFN-alpha is predominantly detected in B cells. Activation of Stat6 by IFN-alpha in B cells is accompanied by the formation of novel Stat2:Stat6 complexes, including an IFN-stimulated gene factor 3-like complex containing Stat2, Stat6, and p48. B cell lines resistant to the antiproliferative effects of IFN-alpha display a decrease in the IFN-alpha-mediated activation of Stat6. Activation of Stat6 as well as of Stat2:Stat6 complexes by IFN-alpha in B cells may allow modulation of target genes in a cell type-specific manner.
Gupta
S
S
Department of Medicine, Columbia University, New York 10032, USA.
Jiang
M
M
Pernis
A B
AB
D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000494:pharmacology*; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D050795:STAT2 Transcription Factor; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D046911:Macromolecular Substances; D010750:Phosphoproteins; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators