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Does nicotine alter intercellular communication pathways?

Institution: University of California, San Diego
Investigator(s): Ching-Yi Chen, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6FT-0135 Award: $68,864
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
It has become clear that cigarette smoking increases the risk of developing cancer, cardiovascular disease, and allergic-like symptoms. One hypothesis suggests that cigarette smoke increases the permeability of the lung lining, which in turn leads to a possible increase in sensitization to allergens. Several studies have shown an altered immunological response in smokers. In addition, many reports have focused on parental smoking and the development of allergic-like symptoms in their children. These effects of smoking may directly or indirectly result from nicotine, the most important pharmacologically-active substance in tobacco smoke. Therefore, we propose to investigate the regulation of interleukin-2, one of the intercellular signaling proteins which play an important role in allergic reactions, by nicotine. The proposed projects attempts to provide us with information about how smoking can cause allergic-like symptoms in individuals and in children of individuals who smoke tobacco. The present project may also help to explain a general mechanism resulting in inhibitory effects of cigarette smoke on the growth of lung inflammatory cells (specifically T lymphocytes) and may provide us with new targets for screening for novel drugs, which would prove useful for reducing allergic-like symptoms associated with smokers.

Final Report
The purpose of this study is to understand mechanisms that control the stability of one of cytokine gene transcripts, interleukin-2 (IL-2) which plays an important role in allergic reaction including allergic-like symptoms which associate with cigarette smoking. This project is also to determine which intercellular signal is involved in controlling synthesis of IL-2 during activation of T lymphocytes, one type of blood cells which is required for many immune responses.

Studies conducted in the past two year have successfully demonstrated that a specific intercellular communication pathway is involved in stabilization of IL-2 transcripts in activated T cells and have identified an element within the IL-2 transcripts that mediates activation-induced stabilization. When this pathway is activated in T cells, an increase in stability of IL-2 transcripts is observed which in turn leads to increase in the synthesis of IL-2. We have also shown that an antiinflammatory drug can block the increased stability of IL-2 transcripts.

The identification of a signaling pathway necessary for stabilization of IL-2 transcripts during T cell activation may provide a strategy for searching agents that can increase or decrease IL-2 transcript stability. We have also identified proteins that are involved in this process which may further provide a target for screening drugs that prevent or enhance function of these proteins which in turn regulates turnover of IL-2 transcripts. These agents or drugs would prove useful -for reducing inflammatory responses and allergic-like symptoms associated with cigarette smoking, for the therapy of asthma and arthritis, or for the prevent or treatment of tobacco-related diseases such as lung cancer.

Stabilization of interleukin-2 mRNA through the c-Jun N-terminal kinase pathway
Periodical: Science Index Medicus:
Authors: Chen C-Y, Del Gatto Konczak F, Wu Z, Karin M ART
Yr: 1998 Vol: 280 Nbr: Abs: Pg: 1945-1949