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Progesterone-Induced Blocking Factor Activates STAT6 via Binding to a Novel IL-4 Receptor¹

Noemi Kozma^*, Melinda Halasz^*, Beata Polgar^*, Tobias G. Poehlmann^¶, Udo R. Markert^¶, Tamas Palkovics^*, Marton Keszei^||, Gabriella Par^*, Katalin Kiss, Jozsef Szeberenyi, Laszlo Grama and Julia Szekeres-Bartho^2,*,

^* Department of Medical Microbiology and Immunology, Department of Biology, Department of Biophysics, and Reproductive and Tumor Immunology Research Group of the Hungarian Academy of Sciences, Pecs University, Pecs, Hungary; ^¶ Friedrich-Schiller University, Jena, Germany; and ^|| Department of Genetics, Cellular, and Immunobiology, Semmelweis University, Medical School, Budapest, Hungary

Progesterone-induced blocking factor (PIBF) induces Th2-dominant cytokine production. Western blotting and EMSA revealed phosphorylation as well as nuclear translocation of STAT6 and inhibition of STAT4 phosphorylation in PIBF-treated cells. The silencing of STAT6 by small interfering RNA reduced the cytokine effects. Because the activation of the STAT6 pathway depends on the ligation of IL-4R, we tested the involvement of IL-4R in PIBF-induced STAT6 activation. Although PIBF does not bind to IL-4R, the blocking of the latter with an Ab abolished PIBF-induced STAT6 activation, whereas the blocking of the IL-13R had no effect. PIBF activated suppressor of cytokine signaling-3 and inhibited IL-12-induced suppressor of cytokine signaling-1 activation. The blocking of IL-4R counteracted all the described effects, suggesting that the PIBF receptor interacts with IL-4R -chain, allowing PIBF to activate the STAT6 pathway. PIBF did not phosphorylate Jak3, suggesting that the -chain is not needed for PIBF signaling. Confocal microscopic analysis revealed a colocalization and at 37°C a cocapping of the FITC PIBF-activated PIBF receptor and PE anti-IL-4R-labeled IL-4R. After the digestion of the cells with phosphatidylinositol-specific phospholipase C, the STAT6-activating effect of PIBF was lost, whereas that of IL-4 remained unaltered. These data suggest the existence of a novel type of IL-4R composed of the IL-4R -chain and the GPI-anchored PIBF receptor.

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