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.

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Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARa, -d, and -g, which are members of the steriod receptor superfamily. The ®rst member of the family (PPARa) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. De®ned functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARa being involved in b-oxidation pathways, and PPARg in the di erentiation of adipocytes. Little is known about the functions of PPARd, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clo®brate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the ®eld of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands.

Objective— The role of the nuclear receptor peroxisome-proliferator activated receptor (PPAR)-β/δ in endothelial cells remains unclear. Interestingly, the selective PPARβ/δ ligand GW501516 is in phase II clinical trials for dyslipidemia. Here, using GW501516, we have assessed the involvement of PPARβ/δ in endothelial cell proliferation and angiogenesis. Methods and Results— Western blot analysis indicated PPARβ/δ was expressed in primary human umbilical and aortic endothelial cells, and in the endothelial cell line, EAHy926. Treatment with GW501516 increased human endothelial cell proliferation and morphogenesis in cultures in vitro, endothelial cell outgrowth from murine aortic vessels in vitro, and angiogenesis in a murine matrigel plug assay in vivo. GW501516 induced vascular endothelial cell growth factor mRNA and peptide release, as well as adipose differentiation-related protein (ADRP), a PPARβ/δ target gene. GW501516-induced proliferation, morphogenesis, vascular endothelial growth factor (VEGF), and ADRP were absent in endothelial cells transfected with dominant-negative PPARβ/δ. Furthermore, treatment of cells with cyclo-VEGFI, a VEGF receptor1/2 antagonist, abolished GW501516-induced endothelial cell proliferation and tube formation. Conclusions— PPARβ/δ is a novel regulator of endothelial cell proliferation and angiogenesis through VEGF. The use of GW501516 to treat dyslipidemia may need to be carefully monitored in patients susceptible to angiogenic disorders.