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Regulation of cytokine production in pulmonary inflammation

Institution: University of California, San Diego
Investigator(s): Wen Ming Chu, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9KT-0067 Award: $93,268
Subject Area: Pulmonary Disease
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
Repeated exposure to either firsthand or second-hand tobacco smoke results in the development or worsening of asthma. In early life, children of mothers who smoke have a higher incidence of wheezing illness, elevated serum immunoglobulin (IgE) and greater airway responsiveness to allergen challenge. Children exposed postpartum to secondhand smoke have an increased risk for persistent wheezing and atopic disease, especially allergic asthma.

Allergic asthma is a pulmonary disease in which acute episodes of bronchial obstruction occur in conjunction with an underlying persistent abnormality in response to allergen challenge. A cardinal feature of allergic asthma is bronchial hypersensitivity and airway inflammation, and a correlation between IgE level and severity or occurrence of asthma, especially in children. Many cell types present in the lungs of asthmatics are capable of binding IgE via the lung affinity IgE binding protein (receptor). This receptor is upregulated on white blood cells, platelets, inflammatory cells and alveolar macrophages (scavenger cells) of asthmatics. It is believed that allergens initiate an asthmatic process by triggering IgE-bearing pulmonary inflammatory cells to release various mediators that can attract and stimulate additional inflammatory cells, resulting in bronchoconstriction, increased airway resistance and worsening asthma.

Accumulation of evidence reveals that immunostimulatory synthetic oligonucleotides (ISS) potentially suppress this response via induced proteins (cytokines) such as interferons and interleukins. For example, in a mouse model of allergic asthma, ISS inhibited airway hypersensitivity and allergic inflammation by activating macrophages, natural killer (NK) cells and dendritic cells (DC) to produce cytokines that inhibit synthesis of IgE and other mediators of bronchoconstriction, thereby playing a pivotal role in suppressing allergic response. However, the underlying molecular mechanisms of ISS-mediated effects are not yet identified.

We plan to investigate the molecular components that are involved in the ISS-mediated inhibition of IgE secretion by inflammatory cells. Putative important players are transcription factors, active protein 1 (AP-1) and nuclear factor (NF-B), which regulate the synthesis of many other proteins that are important for suppressing the inflammatory response. Exactly how ISS activate AP-1 and NF-kB is not clear. The knowledge gained from detailed information of the mechanisms will allow us to develop better DNA vaccination-based immunotherapy for inflammatory lung diseases such as asthma caused by exposure to tobacco smoke.

Final Report
Asthma is a pulmonary disease in which acute episodes of bronchial obstruction occur in conjunction with an underlying persistent abnormality inresponse to challenges. A cardinal feature of asthma is bronchial hypersensitivity and airway inflammation. Inflammation includes influx of neutrophils, eosinophils, basophils, lymphocytes and monocytes. The inflammatory cells secrete a variety of mediators, such as IgE, and hormones that can attract and stimulate additional inflammatory cells, resulting in bronchocontraction, increased airway resistance and worsening asthma.

Biod and Raz reported that synthetic immunostimulatory oligonucleotides (ISS-ODN) inhibited airway hypersensitivity and the late phase reaction of allergic inflammation by influencing innate immunity in a mouse model of asthma. Macrophages, natural killer (NK) cells and dentdric cells are the most important components of innate immunity. These cells are selectively activated by ISS-ODN to inhibit proteins that inhibit synthesis of IgE and mediators of asthma, and therefore playing an important role in suppressing inflammatory reaction. However, molecular mechanism of action of ISS-ODN is not well understood. In this proposed research, we identified that a protein complex, DNA-PK, is required for the production of ISS-ODN-induced proteins that inhibit mediators of inflammatory reaction. We demonstrated that DNA-PK is required for the activation of a transcription factor, NF-KB, and its upstream protein, IKK, which regulate the synthesis of many other proteins that are important for suppressing the inflammatory response. We plan to investigate whether DNA-PK is required for the activation of another transcription factor AP-1, which also regulates the synthesis of many other proteins that are important for suppressing the inflammatory response. Furthermore, we will identify the relationship between DNA-PK and the receptor protein TLR9, and investigate their roles in the inhibition of inflammatory reaction.
Publications

DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA
Periodical: Cell Index Medicus:
Authors: Chu WM, Gong X, Li ZW, et al ART
Yr: 2001 Vol: 103 Nbr: Abs: Pg: 909-918