Regulation of Allergic Asthma by TGF-beta-induced Modulation of mMCP-1 and mMCP-4

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DESCRIPTION (provided by applicant): Transforming growth factor-beta (TGF-beta) has been strongly implicated in the development of allergic asthma. Mast cell degranulation also plays a key role in exacerbating allergic asthma, and is the therapeutic target of both leukotriene antagonists and anti-IgE antibodies. Recent data from our laboratory has suggested that mice lacking the alpha v beta6 integrin, which modulates TGF-beta activity, are protected from airway hyperreactivity. Furthermore, this effect is mediated by differential mast cell protease expression induced by TGF-beta, namely via the upregulation of mMCP-1 and the downregulation of mMCP-4. These proteases have been shown to influence airway hyperreactivity, with mMCP-1 augmenting smooth muscle contraction in response to methacholine and mMCP-4 inhibiting IL-13 induced contraction. In this proposal we will systematically investigate the mechanism by which mMCP-1 and mMCP-4 affect contractile response using parallel experimental systems (tracheal ring contraction in muscle bath and airway narrowing in lung slices). We will use constructs of mMCP-1-, and mMCP-4- knockout mice to assess what contribution the interaction of TGF-beta with mast cells makes to the contractile response. We propose to determine whether mMCP-1 and mMCP-4 act directly on smooth muscle or indirectly via adjacent epithelial cells. Since force generation in smooth muscle depends on Ca2+-dependent actin-myosin cross-bridging, we will also investigate how mMCP-1 and mMCP-4 modulate Ca2+ homeostasis. The proposed studies will elucidate the mechanism by which TGF-beta-modulated expression of mast cell proteases mMCP-1 and mMCP-4 affect airway hyperreactivity. As this pathway plays an important role in the pathogenesis of allergic asthma, a more thorough understanding will provide potential targets for future therapy.