Signaling Pathway of IL-1Beta Induced TGFBeta Activation

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DESCRIPTION (provided by applicant): IL-1beta and TGFbeta are cytokines involved in pulmonary fibrosis and acute lung injury (ALl). Transient overexpression of IL-1beta in rat lungs induces pulmonary fibrosis associated with persistently elevated active TGFbeta levels in bronchoalveolar lavage samples, suggesting that TGF( activation can be a downstream effect of IL-1beta. The epithelial specific alphavbeta6 integrin regulates fibrosis and ALl by activating TGFbeta. Preliminary studies from our laboratory show that alphavbeta6-dependent TGFbeta activation is regulated by focal adhesion kinase (FAK), PI3 kinase, and the Rho family of small GTPases, all signaling molecules that are involved in IL-1beta signaling. Rat alveolar epithelial cells cultured in vitro activate TGFbeta through the alphavbeta6 integrin after stimulation with IL- 1beta. Our main hypothesis is that IL-1beta stimulation in vitro results in beta6-dependent TGFbeta activation through a signaling cascade involving FAK, PI3K and the Rho family of small GTPases. In addition, we hypothesize that IL-1( induces pulmonary fibrosis in mice in vivo by beta6-dependent TGFbeta activation. To identify this signaling cascade we will use pharmacological inhibitors and adenoviral transfer of constitutively active and dominant negative gene constructs of FAK, PI3K, Rac1, and RhoA in our in vitro model of rat alveolar epithelial cells. To elucidate the in vivo role of beta6-dependent TGFbeta activation in IL-1beta induced pulmonary fibrosis, we will transiently over-express IL- 1beta in the lungs of control, beta6 null (-/-) mice, and mice pre-treated with alphavbeta6 blocking antibody and assess the extent of pulmonary fibrosis. These studies should provide insight into the pathway involved in lung fibrosis and ALI while identifying new therapeutic targets for these common lung disorders.