In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 7 ( 2005-04-01), p. 2956-2963
Abstract:
Interleukin (IL)-4 exhibits antitumor activity in rodent experimental gliomas, which is likely mediated by the actions of IL-4 on a variety of immune cells present in and around the tumor masses. Here, we show that IL-4, which activates Stat6 in normal human astrocytes and in a variety of other cells, induces an aberrant activation of Stat3 in glioblastoma multiforme (GBM) cells but not in normal human astrocytes. Previously, we have shown that autocrine IL-6 signaling induces a persistent activation of Stat3. Now, we show that Stat3 is further activated by IL-4 stimulation of GBM cells. Expression of IL-13Rα2, a decoy receptor for IL-13 that partly blocks IL-4–mediated activation of Stat6 in GBM cells, up-regulates the activation of Stat3 as shown by a small interfering RNA–mediated inhibition of IL-13Rα2 expression. In addition, transient expression of the IL-13Rα2 transgene in 293T cells increases the IL-4–mediated activation of Stat3 and subsequent expression of Stat3-targeted gene. Coimmunoprecipitation results reveal that IL-13Rα2–mediated activation of Stat3 does not require a direct physical interaction between Stat3 and IL-13Rα2. Chromatin immunoprecipitation assay employing anti-Stat3 antibody confirms the in vivo binding of activated Stat3 to the promoters of genes that encode antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1. IL-4 significantly up-regulates of the steady-state levels of Bcl-2, Bcl-xL, and Mcl-1 in GBM cells. These results indicate that IL-4/IL-13 receptor-mediated Stat3 signaling may contribute to the pathogenesis of GBM cells by modulating the expression of the Bcl-2 family of antiapoptotic proteins.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-04-3592
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2005
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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