Aberrant Stat3 signaling by interleukin-4 in malignant glioma cells: involvement of IL-13Ralpha2.
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-13Ralpha2, 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-13Ralpha2 expression. In addition, transient expression of the IL-13Ralpha2 transgene in 293T cells increases the IL-4-mediated activation of Stat3 and subsequent expression of Stat3-targeted gene. Coimmunoprecipitation results reveal that IL-13Ralpha2-mediated activation of Stat3 does not require a direct physical interaction between Stat3 and IL-13Ralpha2. 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.
Rahaman
Shaik Ohidar
SO
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio 44195, USA.
Vogelbaum
Michael A
MA
Haque
S Jaharul
SJ
D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000502:physiology*; D053660:Receptors, Interleukin-13; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D019076:Transgenes; D015854:Up-Regulation; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; C508181:IL13RA1 protein, human; D053661:Interleukin-13 Receptor alpha1 Subunit; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D051020:bcl-X Protein; D015847:Interleukin-4