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Molecular & Cellular Proteomics 6:238-251, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Interleukin-4 Inhibits Caspase-3 by Regulating Several Proteins in the Fas Pathway during Initial Stages of Human T Helper 2 Cell Differentiation^*,S

Kirsi J. Rautajoki^,,¶, Elisa M. Marttila, Tuula A. Nyman^,|| and Riitta Lahesmaa

From the Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Tykistökatu 6A, 5th floor, FIN-20521 Turku, Finland, ^|| Institute of Biotechnology, P. O. Box 56, University of Helsinki, FIN-00014 Helsinki, Finland, and Turku Graduate School of Biomedical Sciences, University of Turku, Kiinamyllynkatu 13, FIN-20520 Turku, Finland

Interleukin-4 (IL-4) is the main cytokine that polarizes activated naïve CD4⁺ T cells in the T helper 2 (Th2) direction. IL-4 also regulates the subsequent stages of Th2 cell-mediated diseases, such as allergies. We conducted a proteomics study to identify IL-4-induced differences during the initial stages of T helper cell differentiation. Primary CD4⁺ T lymphocytes were isolated from human cord blood, activated through CD3 and CD28, and cultured in the presence or absence of IL-4. Soluble proteins were separated by two-dimensional electrophoresis and visualized by staining with autoradiography, which indicated that at least 20 proteins might be regulated by IL-4. From this minimum of 20 stained proteins, altogether 35 proteins were identified using tandem mass spectrometry. Interestingly the fragmented form of GDP dissociation inhibitor expressed in lymphocytes/Rho GDP dissociation inhibitor 2 (Ly-GDI), a known target of Caspase-3, was observed to be down-regulated in IL-4-treated cells. It was shown in further studies that IL-4 decreases Caspase-3 activity and cell death in these cells. Neutralizing Fas-Fas ligand interaction led to decreased Caspase-3 activity and lowered Ly-GDI fragmentation. We further characterized the effects of IL-4 on the expression of main regulators in the Fas-mediated pathway. We demonstrated that IL-4 decreases expression of Fas receptor and increases expression of Bid, Bcl-2, and Bcl-xL. Importantly IL-4 significantly up-regulated the short form of c-FLIP, although the levels of c-FLIP long were unaltered after IL-4 induction. Taken together, our results indicate that IL-4 inhibits caspase activity during the initial stages of human Th2 cell differentiation by regulating expression of several key players in the Fas-induced pathway.

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