The interleukin 4 receptor alpha chain (IL-4Ra) plays a key role in allergic inflammatory responses. However, whereas the function of its dedicated transcription factor Stat6 in promoting allergic inflammation is well established, those of the other two signaling branches down-stream of the IL-4Ra I4R and ITIM motifs remains unclear. By employing a targeted gene knock-in approach that inactivated the I4R motif by mutagenesis of its effector tyrosine residue into phenylalanine (Y500F), we have demonstrated novel tissue and ligand-specific functions of this motif. The Y500F mutation enhanced antigen-driven antibody responses and allergic airway inflammation, consistent with a negative regulatory function of the I4R motif in receptor signaling. Remarkably however, I4R mutagenesis selectively impaired two cardinal effects of DL-13 on resident airway tissues, including induction of airway hyper-responsiveness (AHR) and metaplasia of primary tracheal epithelial cell cultures into goblet cells, while sparing the induction of the same events by IL-4. To examine the mechanism of enhanced antibody response in Y500F mutants, we propose to test the hypothesis that the I4R motif down-regulates IL-4Ra signaling in B cells and identify the molecular basis of this function. To probe the function of the I4R motif in IL-13 signaling in resident airway tissues, we propose to examine the hypothesis that signaling via the I4R motif mediates key EL-13 responses in airway epithelial cells relevant to AHR and goblet cell metaplasia, and that it mediates aspects of IL-13-dependent chronic structural airway changes. Finally, we propose to employ newly derived mice in which the ITIM motif has been inactivated by mutagenesis of its effector tyrosine residue (Y709F) to address the in vivo function of this motif in IL-4Ra signaling and allergic inflammation. These studies will identify fundamental regulatory mechanisms involved in allergic inflammation and help devise targeted interventions in related medical conditions including asthma. ? ?
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