BIOLOGY OF IL-16 IN IL-1680 AND IL-1614 TRANSGENIC MICE

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IL-16 os a cytokine produced by bronchial epithelium which induces motile responses in CD bearing cells, and is detectable in bronchoalveolar lavage fluid of asthmatics. We have identified an 80 kDA IL-16 precursor molecule, IL-16/80 from which bioactive IL-16/14 is cleaved. The biologic activities, in asthma and processing mechanisms of IL-16/80 are unknown. We have initiated studies to characterize the in vivo effector functions of IL-16 by generating the first transgenic mice which target IL-16/14 to the bronchial epithelium. Transgene positive positive animals produce and secrete bioactive IL-16 at baseline in exaggerated amounts after challenge with serotonin. Transgenic animals also develop enhanced inflammation, airway mucous, IFN-gamma, IL-6, and JE/MCP-1 after RSV infections. In this grant we propose to use these mice and IL-16/80 transgenics to characterize the in vivo effects, processing in the normal and inflamed airway. We will: Aim 1: Characterize the CC10-IL-16/14 transgenic mice by defining their histology, immunology and physiology and the IL-16 moieties produced in these animals at baseline and after serotonin challenge. Aim 2. Characterize the responses of CCC-10-IL-16/14 mice to ovalbumin and respiratory syncytial virus induced airway inflammation and the IL-16 moieties produced in these models. Aim 3: Generate and characterize IL- 16/80 transgenic mice in which the CC10 promoter is used to over-express IL-16/80 in the lung. We will characterize the phenotype of these animals at baseline and after serotonin challenge and the IL-16 moieties produced by these animals. Aim 4: Characterize the responses of C-10-11- 16/80 mice to ovalbumin and respiratory syncytial virus induced airway inflammation and the IL-16 moieties produced in these models. In these experiments we will characterize the in vivo the effector functions of the C-terminal bioactive form of IL-16 (IL-16/14) and IL-16/80 at baseline and ruing inflammatory stress. We will characterize the IL-16 moieties in the lungs of these animals at baseline and in the setting of inflammation. These studies will provide profound insights into the biologic effector functions of IL-16 and the mechanisms of processing of the IL-16 pro-hormone in health and disease. The experience and techniques I will gain in achieving the goals outlined in this proposal will compliment my previous research experience and will help me grow as a scientist and ultimately become an independent investigator. These finding swill have impressive implications via-a-vis our knowledge of the biology of IL-16 and mechanisms of airway inflammation and healing in asthma.