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Aberrant Stat3 Signaling by Interleukin-4 in Malignant Glioma Cells: Involvement of IL-13R2

¹ Department of Cancer Biology, Lerner Research Institute; ² Brain Tumor Institute; ³ Department of Neurosurgery; and⁴ Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio

Requests for reprints: S. Jaharul Haque, Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, NB-40, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-445-6622; Fax: 216-445-6269; E-mail: haquej{at}ccf.org.

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-13R2, 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-13R2 expression. In addition, transient expression of the IL-13R2 transgene in 293T cells increases the IL-4–mediated activation of Stat3 and subsequent expression of Stat3-targeted gene. Coimmunoprecipitation results reveal that IL-13R2–mediated activation of Stat3 does not require a direct physical interaction between Stat3 and IL-13R2. 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-x_L, and Mcl-1. IL-4 significantly up-regulates of the steady-state levels of Bcl-2, Bcl-x_L, 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.

Key Words: Glioblastoma • IL-4 • IL-13R2 • Stat3 • apoptosis • survival

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