Mechanisms of Nicotine Induced Immunosuppression

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by the applicant): Among the deleterious effects associated with the use of tobacco products is the suppression of the immune function. Preliminary data demonstrates that nicotine, and its major metabolite cotinine, inhibit the expression and activity of cyclin-dependent kinase 4 (Cdk4). The inhibition of Cdk4 by nicotine and cotinine presents a potential mechanistic link between tobacco use and immune system dysfunction; the repression of Cdk4 by nicotine and cotinine induces cytokine unresponsiveness leading to immune system tolerance (or anergy). Hypothesis: Nicotine and cotinine exert immunosuppressive effects principally by repressing Cdk4 gene transcription and by altering Ckl interact ions. These actions are transduced through nicotinic acetylcholine receptors, involving calcium signaling, calcineurin and NFATI. This hypothesis will be tested with the following specific aims (1) Determine the extent and the mechanism(s) of the nicotine and cotinine induced repression of Cdk4 expression and competence induction, (2) Define the signaling pathway, cell surface receptor(s), and intervening molecules involved in the nicotine and cotinine induced repression of Cdk4. Both effects at the protein level by immuno-blot, and RNA level by RNase protection, will be explored in primary human T cells, with additional techniques including, receptor antagonist, electrophorectic mobility shift assay and array analysis.