The vitronectin RGD motif regulates TGF-ß-induced alveolar epithelial cell apoptosis.

Transforming growth factor-ß (TGF-ß) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-ß, which regulates changes in the cellular and matrix makeup of the lung during the repair and fibrosis phase. TGF-ß can also initiate alveolar epithelial cell (AEC) apoptosis. Injury leads to destruction of the laminin-rich basement membrane, which is replaced by a provisional matrix composed of arginine-glycine-aspartate (RGD) motif-containing plasma matrix proteins, including vitronectin and fibronectin. To determine the role of specific matrix proteins on TGF-ß-induced apoptosis, we studied primary AECs cultured on different matrix conditions and utilized mice with deletion of vitronectin (Vtn(-/-)) or mice in which the vitronectin RGD motif is mutated to nonintegrin-binding arginine-glycine-glutamate (RGE) (Vtn(RGE/RGE)). We found that AECs cultured on fibronectin and vitronectin or in wild-type mouse serum are resistant to TGF-ß-induced apoptosis. In contrast, AECs cultured on laminin or in serum from Vtn(-/-) or Vtn(RGE/RGE) mice undergo robust TGF-ß-induced apoptosis. Plasminogen activator inhibitor-1 (PAI-1) sensitizes AECs to greater apoptosis by disrupting AEC engagement to vitronectin. Inhibition of integrin-associated signaling proteins augments AEC apoptosis. Mice with transgenic deletion of PAI-1 have less apoptosis after bleomycin, but deletion of vitronectin or disruption of the vitronectin RGD motif reverses this protection, suggesting that the proapoptotic function of PAI-1 is mediated through vitronectin inhibition. Collectively, these data suggest that integrin-matrix signaling is an important regulator of TGF-ß-mediated AEC apoptosis and that PAI-1 functions as a natural regulator of this interaction.

Transcriptional regulation of CD4+ TH cells that mediate tissue inflammation.

Acquired and genetic immunodeficiencies have revealed an indispensable role for CD4+ T cells in the induction of protective host immune responses against a myriad of microbial pathogens. Influenced by the cytokines present in the microenvironment, activated CD4+ T cells may differentiate into several highly-specialized helper subsets defined by the production of distinct signature cytokines tailored to combat diverse classes of pathogens. The process of specification and differentiation is controlled by networks of core, master, and accessory transcription factors, which ensure that CD4+ T helper (TH ) cell responses mounted against an invading microbe are of the correct specificity and type. However, aberrant activation or inactivation of transcription factors can result in sustained and elevated expression of immune-related genes, leading to chronic activation of CD4+ TH  cells and organ-specific autoimmunity. In this review, we provide an overview of the molecular basis of CD4+ TH  cell differentiation and examine how combinatorial expression of transcription factors, which promotes genetic plasticity of CD4+ TH  cells, can contribute to immunological dysfunction of CD4+ TH responses. We also discuss recent studies which highlight the potential of exploiting the genetic plasticity of CD4+ TH  cells in the treatment of autoimmune and other immune-mediated disorders.