Cyclooxygeuase (COX) progressively, also peakingatday 14. COX-1 protein remained unaltered throughout. The iNOS activity increased over the first 24 h in the skin, with a further major increase in the granulomatous tissue between days 3 and 7, followed by a decrease at day 14 and a further increase at day 21. The rise in COX and NOS activities in the skin during the acute phase reinforces the proinflammatory role for prostanoids and suggests one also for nitric oxide. However, in the chronic and resolving stages, a dio of COX and NOS activity occurred. Thus, there may be differential regulation of these enzymes, perhaps due to the changing pattern of cytokines during the inflammatory response.

Our functional evaluation of AIP mutations is consistent with a tumor-suppressor role for AIP and its involvement in familial acromegaly. The abnormal expression and subcellular localization of AIP in sporadic pituitary adenomas indicate deranged regulation of this protein during tumorigenesis.

The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors belonging to the nuclear receptor superfamily. Until recently, the genes regulated by PPARs were those believed to be predominantly associated with lipid metabolism. Recently, an immunomodulatory role for PPARγ has been described in cells critical to the innate immune system, the monocyte/macrophage. In addition, evidence for an antiinflammatory role of the PPARγ ligand, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) has been found. In the present studies, we demonstrate, for the first time, that murine helper T cell clones and freshly isolated splenocytes express PPARγ 1. The PPARγ expressed is of functional significance in that two ligands for PPARγ, 15d-PGJ2 and a thiazolidinedione, ciglitazone, mediate significant inhibition of proliferative responses of both the T cell clones and the freshly isolated splenocytes. This inhibition is mediated directly at the level of the T cell and not at the level of the macrophage/APC. Finally, we demonstrate that the two ligands for PPARγ mediate inhibition of IL-2 secretion by the T cell clones while not inhibiting IL-2-induced proliferation of such clones. The demonstration of the expression and function of PPARγ in T cells reveals a new level of immunoregulatory control for PPARs and significantly increases the role and importance of PPARγ in immunoregulation.

15-Deoxy-⌬12,14 -prostaglandin J 2 (15d-PGJ 2 ) is a bioactive prostanoid produced by dehydration and isomerization of PGD 2 , a cyclooxygenase product. It was recently shown to activate the nuclear peroxisome proliferatoractivated receptor ␥ (PPAR␥), a critical transcription factor involved in adipocyte and monocyte differentiation. In this report, we show that 15d-PGJ 2 is a potent inducer of caspase-mediated endothelial cell apoptosis. PPAR␣, -␦, and -␥ were expressed by endothelial cells, which, when treated with 15d-PGJ 2 , induced receptor translocation into the nucleus, and an increase in PPAR response element-driven reporter gene expression. Ciglitizone, a selective activator of PPAR␥, also induced transcriptional activation and endothelial cell apoptosis. Endothelial apoptosis induced by 15d-PGJ 2 was inhibited by treatment of cells with an oligonucleotide decoy to a consensus PPAR response element sequence. Furthermore, overexpression of the PPAR␥ isotype induced endothelial cell apoptosis, which was further potentiated by 15d-PGJ 2 treatment. We conclude that 15d-PGJ 2 induces endothelial cell apoptosis via a PPARdependent pathway. The PPAR pathway may be a therapeutic target for numerous pathologies in which excessive angiogenesis is implicated.

No abstract