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Novel Involvement of the Immunomodulator AS101 in IL‐10 Signaling, via the Tyrosine Kinase Fer
Author(s) -
HAYUN RAMI,
SHPUNGIN SALI,
MALOVANI HANA,
ALBECK MICHAEL,
OKUN EITAN,
NIR URI,
SREDNI BENJAMIN
Publication year - 2007
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1397.028
Subject(s) - autocrine signalling , stat3 , tyrosine phosphorylation , cancer research , phosphorylation , tyrosine kinase , cytokine , paracrine signalling , signal transduction , chemistry , cell culture , immunology , biology , biochemistry , receptor , genetics
: Interleukin‐10 (IL‐10) plays a major proliferative role in many tumors, and activates the transcription factor Stat3 by tyrosine phosphorylation. The immunomodulator ammonium trichloro (dioxoethylene‐o,o') tellurate (AS101) has a direct antitumor activity, and is able to sensitize several tumors to chemotherapy, by inhibiting the tumor IL‐10 autocrine loop. The tyrosine kinase Fer is essential for the proliferation of numerous malignant cell lines and in some cases was related to Stat3 activation. This article examined the role of AS101 in IL‐10 signaling, and the correlation between Fer and Stat3, in human peripheral blood mononuclear cells (PBMC). We show that Fer was associated with Stat3 in PBMC and RAW 264.7, a macrophage cell line. Recombinant IL‐10 (rIL‐10) increased the tyrosine phosphorylation of Stat3, upregulated the levels of Fer, and increased the association of Fer with phosphorylated Stat3 (pYStat3). All the activities of IL‐10 mentioned above were reversed by AS101. The effects conferred by AS101 were totally abolished by exogenous addition of rIL‐10. These results indicate that AS101 downregulates the Stat3 IL‐10 loop, and inhibits Fer association with pYStat3. We conclude that anti‐IL‐10 treatment using AS101, may be beneficial in certain malignancies and other pathologies in which IL‐10 secretion is elevated and Stat3 is continuously phosphorylated.