More specifically, a recent study investigating the respective roles of COX-1 and COX-2 in the course of disease in a dextran sulfate selleckchem Nintedanib sodium model of colitis demonstrated that COX-2 was critical for protection against ulceration in a later stage of disease (60). The finding that COX-2 is a survival effector of TNF-transactivated EGFR also has relevance to cancers of the GI tract, since chronic inflammatory conditions provide an environment that permits the development and progression of cancers. For example, prolonged ulcerative colitis is a known risk factor for the development of epithelial dysplasia and adenocarcinoma (44, 55). Also, studies of colitis-associated neoplasia in humans show COX-2 overexpression in neoplastic lesions (1).

Furthermore, in an animal model of colitis-associated cancer, increased mucosal EGFR phosphorylation and COX-2 expression have been reported (21). This correlation between EGFR phosphorylation and increased COX-2 expression in an inflammatory environment is certainly consistent with our results, and it may define a mechanism that explains the different outcomes of tissue toward ulceration or neoplasia. It is possible that sites of ulceration in IBD represent compartments of tissue where COX-2, which is protective, is not adequately expressed in response to TNF as a result of a lack/dysregulation of components of a TNFR-EGFR-COX-2 axis. In contrast, sites at which neoplasias develop may represent compartments where COX-2 is expressed in large quantities as a result of adequate or overactive components of this axis.

For instance, our data suggest that tissues that lack TNFR2 expres
the pathogenesis of type 2 diabetes mellitus is characterized by both insulin resistance and insulin deficiency. Our understanding of the molecular causes involved in defective insulin secretion from the ��-cell is limited. However, it is clear that impaired insulin secretion may be due, at least in part, to a reduced number of docked granules at the plasma membrane (31, 41). In the ��-cell, emerging evidence implicates the regulation of the filamentous actin (F-actin) network and phosphatidylinositol-4,5-bisphosphate (PIP2) as critical factors regulating late stage processes of insulin granule trafficking and secretion (32, 46�C47). Crosstalk and colocalization has been described between F-actin and PIP2 in ��-cells (47). Additionally, F-actin associates with the soluble N-ethylmaleimide-sensitive factor AV-951 attachment protein receptor (SNARE) proteins syntaxin-1A and syntaxin-4, and the syntaxin-4 association with F-actin is a negative regulator of insulin secretion (20).