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Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation.

Authors :
Cho SS
Bacon CM
Sudarshan C
Rees RC
Finbloom D
Pine R
O'Shea JJ
Source :
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 1996 Dec 01; Vol. 157 (11), pp. 4781-9.
Publication Year :
1996

Abstract

The immunoregulatory cytokine IL-12 plays a central role in cell-mediated immune responses through its effects on NK cells and T lymphocytes. While IL-12 is known to share some functions with other cytokines, such as IFN-alpha, it also maintains distinct roles, such as its ability to induce Th1 differentiation. The molecular basis for these unique and overlapping functions is not well understood. IL-12 has previously been shown to induce tyrosine phosphorylation and DNA-binding of STAT3 and STAT4, members of the signal transducers and activators of transcription (STAT) family. Because STAT4 has only been shown to be activated in response to IL-12, this specificity has been suggested to be a basis for the unique actions of IL-12. In this study, we demonstrated that STAT4 activation by IL-12 is not unique; IL-12 and IFN-alpha, but not IFN-gamma, induced tyrosine phosphorylation and DNA binding of STAT4. Since tyrosine and serine phosphorylation of STAT1 have previously been shown to be important in IFN-alpha-mediated signaling, we also investigated IL-12- and IFN-alpha-induced serine phosphorylation of STAT4. We demonstrated that both cytokines induced serine phosphorylation. This modification was not required for DNA binding, but may be important in STAT-mediated transcription. Thus, STAT4 activation was not IL-12 specific, and IL-12 and IFN-alpha activated STAT4 through both tyrosine and serine phosphorylation. These findings have significant implications for understanding the role of STAT4 in mediating biologic functions; specifically, the data argue that the unique effects of IL-12 cannot be solely explained by STAT4 activation.

Details

Language :
English
ISSN :
0022-1767
Volume :
157
Issue :
11
Database :
MEDLINE
Journal :
Journal of immunology (Baltimore, Md. : 1950)
Publication Type :
Academic Journal
Accession number :
8943379