Activated Human T Lymphocytes Express Cyclooxygenase-2 and Produce Proadipogenic Prostaglandins that Drive Human Orbital Fibroblast Differentiation to Adipocytes

Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA.
American Journal Of Pathology (Impact Factor: 4.59). 11/2006; 169(4):1183-93. DOI: 10.2353/ajpath.2006.060434
Source: PubMed


The differentiation of preadipocyte fibroblasts to adipocytes is a crucial process to many disease states including obesity, cardiovascular, and autoimmune diseases. In Graves' disease, the orbit of the eye can become severely inflamed and infiltrated with T lymphocytes as part of the autoimmune process. The orbital fibroblasts convert to fat-like cells causing the eye to protrude, which is disfiguring and can lead to blindness. Recently, the transcription factor peroxisome proliferator activated receptor (PPAR)-gamma and its natural (15d-PGJ2) and synthetic (thiazolidinedione-type) PPAR-gamma agonists have been shown to be crucial to the in vitro differentiation of preadipocyte fibroblasts to adipocytes. We show herein several novel findings. First, that activated T lymphocytes from Graves' patients drive the differentiation of PPAR-gamma-expressing orbital fibroblasts to adipocytes. Second, this adipogenic differentiation is blocked by nonselective small molecule cyclooxygenase (Cox)-1/Cox-2 inhibitors and by Cox-2 selective inhibitors. Third, activated, but not naïve, human T cells highly express Cox-2 and synthesize prostaglandin D2 and related prostaglandins that are PPAR-gamma ligands. These provocative new findings provide evidence for how activated T lymphocytes, through production of PPAR-gamma ligands, profoundly influence human fibroblast differentiation to adipocytes. They also suggest the possibility that, in addition to the orbit, T lymphocytes influence the deposition of fat in other tissues.

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    • "Fibroblast transdifferentiation by chemicals has been demonstrated in in vivo and in vitro cell lineages, e.g., osteocytes [11]–[17], condrocytes [18], [19], adipocytes [20], [21] and hepatocytes [22]. Surprisingly, skin fibroblasts were also chemically reprogrammed toward a pluripotent state, demonstrating its extreme plasticity [23], [24]. "
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    ABSTRACT: The conversion of differentiated cells into insulin-producing cells is a promising approach for the autologous replacement of pancreatic cells in patients with type 1 diabetes (T1D). At present, cellular reprogramming strategies encompass ethical problems, epigenetic failure or teratoma formation, which has prompted the development of new approaches. Here, we report a novel technique for the conversion of skin fibroblasts from T1D patients into insulin-expressing clusters using only drug-based induction. Our results demonstrate that skin fibroblasts from diabetic patients have pancreatic differentiation capacities and avoid the necessity of using transgenic strategies, stem cell sources or global demethylation steps. These findings open new possibilities for studying diabetes mechanisms, drug screenings and ultimately autologous transgenic-free regenerative medicine therapies in patients with T1D.
    PLoS ONE 06/2014; 9(6):e100369. DOI:10.1371/journal.pone.0100369 · 3.23 Impact Factor
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    • "PGD2 is considered an immunomodulatory prostaglandin and some of its cyclopentanone PG metabolites, such as 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), are endowed with anti-inflammatory activities (49, 103). Production of PGD2 has been detected in Th2 cells and this was linked to expression of H-PGDS, while L-PGDS has not been identified in any T cell subtype (67, 104, 105). The downstream product of PGD2 dehydration, 15d-PGJ2, has also been detected in human T cell cultures (67). "
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    ABSTRACT: Fatty acids are involved in T cell biology both as nutrients important for energy production as well as signaling molecules. In particular, polyunsaturated fatty acids are known to exhibit a range of immunomodulatory properties that progress through T cell mediated events, although the molecular mechanisms of these actions have not yet been fully elucidated. Some of these immune activities are linked to polyunsaturated fatty acid-induced alteration of the composition of cellular membranes and the consequent changes in signaling pathways linked to membrane raft-associated proteins. However, significant aspects of the polyunsaturated fatty acid bioactivities are mediated through their transformation to specific lipid mediators, products of cyclooxygenase, lipoxygenase, or cytochrome P450 enzymatic reactions. Resulting bioactive metabolites including prostaglandins, leukotrienes, and endocannabinoids are produced by and/or act upon T leukocytes through cell surface receptors and have been shown to alter T cell activation and differentiation, proliferation, cytokine production, motility, and homing events. Detailed appreciation of the mode of action of these lipids presents opportunities for the design and development of therapeutic strategies aimed at regulating T cell function.
    Frontiers in Immunology 02/2014; 5:75. DOI:10.3389/fimmu.2014.00075
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    • "In these heterodimers, when DP signaling is pharmacologically blocked, CRTH2 function is also inhibited, but not vice versa (Sedej et al., 2012). In addition to signaling through the cell surface receptors DP1 and CRTH2, 15d-PGJ2 and PGD2 can also bind the nuclear hormone receptor transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) (Forman et al., 1995; Kliewer et al., 1995; Harris et al., 2002a; Feldon et al., 2006). By activating PPAR-γ, these prostanoids induce differentiation of fibroblasts into fat cells, and it has been shown that this can be pathophysiologically relevant. "
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    ABSTRACT: Eicosanoids are inflammatory mediators primarily generated by hydrolysis of membrane phospholipids by phospholipase A2 to ω-3 and ω-6 C20 fatty acids that next are converted to leukotrienes (LTs), prostaglandins (PGs), prostacyclins (PCs), and thromboxanes (TXAs). The rate-limiting and tightly regulated lipoxygenases control synthesis of LTs while the equally well-controlled cyclooxygenases 1 and 2 generate prostanoids, including PGs, PCs, and TXAs. While many of the classical signs of inflammation such as redness, swelling, pain, and heat are caused by eicosanoid species with vasoactive, pyretic, and pain-inducing effects locally, some eicosanoids also regulate T cell functions. Here, we will review eicosanoid production in T cell subsets and the inflammatory and immunoregulatory functions of LTs, PGs, PCs, and TXAs in T cells.
    Frontiers in Immunology 06/2013; 4:130. DOI:10.3389/fimmu.2013.00130
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