Visit our Expo - Redox and Inflammation signaling 2012

Session III : Protein kinase cascades as therapeutic targets Poster III, 25
Novel Involvement of the Immunomodulator AS101 in IL-10 Signal Transduction, Via
the Tyrosine Kinase Fer
Rami Hayun, Sali Shpungin, Hana Malovani, Michael Albeck, Uri Nir and Benjamin
Sredni
Safdié Institute for AIDS and Immunology Research, Faculty of Life Sciences, Bar-Ilan
University, Ramat-Gan, Israel. E-mail: srednib@mail.biu.ac.il
Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel.
Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel. E-mail:
nir@mail.biu.ac.il
Interleukin-10 (IL-10) plays a major role in proliferation of many tumor cells and activates
the transcription factor Stat3 by tyrosine phosphorylation. The immunomodulator ammonium
trichloro(dioxoethylene-o,o') tellurate (AS101) sensitizes several tumors to chemotherapy, by
inhibiting the tumor IL-10 autocrine loop. The tyrosine kinase Fer, is essential for the
proliferation of some malignant cell-lines and its connection to Stat3 activation
was demonstrated in a few cases. This study examined the role of AS101 in IL-10 signal
transduction and the correlation between Fer and Stat3, in human peripheral blood
mononuclear cells (PBMC). We showed that Fer was associated with Stat3 in PBMC and in
the RAW 264.7 cell line. Recombinant IL-10 increased the tyrosine phosphorylation of Stat3,
up regulated the levels of Fer, and increased the association of Fer with phosphorylated Stat3
(pYStat3). The immunomodulator AS101 as well as IL-10 receptor antagonist, Inhibited IL-
10 secretion, reduced the phosphorylation of Stat3, decreased the levels of Fer protein and
decreased the association between Fer and pYStat3. All AS101 activities were totally
abrogated by exogenous addition of recombinant IL-10. These results indicate that AS101
plays as a negative regulator in IL-10 signal transduction, and able to dephosphorylate the
proto-oncogene Stat3, and modulates the ability of Fer to associate with pYStat3. Therefore,
anti-IL-10 treatment using AS101 may be effective in certain malignancies and other
pathologies where IL-10 secretion is elevated and Stat3 is continuously phosphorylated.
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