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Cellular FLIP Long Form-Transgenic Mice Manifest a Th2 Cytokine Bias and Enhanced Allergic Airway Inflammation ¹

Wenfang Wu^*, Lisa Rinaldi, Karen A. Fortner^*, Jennifer Q. Russell^*, Jürg Tschopp, Charles Irvin and Ralph C. Budd^2,*

^* Immunobiology Program and Vermont Lung Center, Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405; and Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland

Cellular FLIP long form (c-FLIP_L) is a caspase-defective homologue of caspase-8 that blocks apoptosis by death receptors. The expression of c-FLIP_L in T cells can also augment extracellular signal-regulated kinase phosphorylation after TCR ligation via the association of c-FLIP_L with Raf-1. This contributes to the hyperproliferative capacity of T cells from c-FLIP_L-transgenic mice. In this study we show that activated CD4⁺ T cells from c-FLIP_L-transgenic mice produce increased amounts of Th2 cytokines and decreased amounts of Th1 cytokines. This correlates with increased serum concentrations of the Th2-dependent IgG1 and IgE. The Th2 bias of c-FLIP_L-transgenic CD4⁺ T cells parallels impaired NF-B activity and increased levels of GATA-3, which contribute, respectively, to decreased IFN- and increased Th2 cytokines. The Th2 bias of c-FLIP_L-transgenic mice extends to an enhanced sensitivity to OVA-induced asthma. Taken together, these results show that c-FLIP_L can influence cytokine gene expression to promote Th2-driven allergic reaction, in addition to its traditional role of blocking caspase activation induced by death receptors.

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The JI 2004 172: 4659-4660. [Full Text]  

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