Inhibition of alpha interferon but not gamma interferon signal transduction by phorbol esters is mediated by a tyrosine phosphatase

Emanuel Petricoin, Michael David, Kenichi Igarashi, Christopher Benjamin, Leona Ling, Susan Goelz, David S. Finbloom, Andrew C. Larner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Previous studies have indicated that the expression of viral oncoproteins, cell transformation, or phorbol ester treatment of cells can inhibit alpha/beta interferon (IFN-α/β)-induced gene expression. The mechanisms by which these promoters of cell growth exert their inhibitory effects vary, but in most instances they involve a disruption of the IFN-α/β-induced transcription complex ISGF3 such that the DNA-binding component of this complex (the 48-kDa ISGF3γ protein) does not bind to the interferon- stimulated response element (ISRE). In this report, we demonstrate that phorbol ester treatment of human peripheral blood monocytes dramatically inhibits activation of lFN-α/β-stimulated early response genes but by a mechanism which does not involve abrogation of the ISRE binding of ISGF3γ. Phorbol ester treatment of monocytes inhibited IFNα-stimulated tyrosine phosphorylation of the transcription factors Stat1α, Stat2, and Stat3 and of the tyrosine kinase Tyk2 but had no effect on IFN-γ activation of Stat1α. IFNα-stimulated tyrosine phosphorylation of Jak1 and the α subunit of the IFN-α receptor were unaffected by phorbol 12-myristate 13-acetate (PMA). Moreover, PMA caused the dephosphorylation of Tyk2 but not of Jak1, which was activated by IFN. Pretreatment of cells with vanadate prevented the effects of PMA with regard to PMA-induced Tyk2 dephosphorylation. These observations suggest that PMA exerts its inhibitory effects by activation of a tyrosine phosphatase which selectively regulates Tyk2 but nut Jak1 activity.

Original languageEnglish
Pages (from-to)1419-1424
Number of pages6
JournalMolecular and Cellular Biology
Issue number4
StatePublished - Apr 1996
Externally publishedYes


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