Article

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

ABSTRACT

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.

    • "This is consistent with a role for Th 1 -related cytokines in the early active inflammatory phase of GO, rather than the late tissue remodeling phase of the disease. Moreover, physical interaction between orbital fibroblasts and autologous T-lymphocytes drives adipogenic differentiation of orbital fibroblasts in a prostaglandin dependent manner (Feldon et al., 2006). When cultured under pathological pressure in a three-dimensional collagen matrix Thy1 À orbital fibroblasts differentiate into adipocytes . "
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    ABSTRACT: Graves' ophthalmopathy (GO) is an extra-thyroidal complication of Graves' disease (GD; Graves' hyperthyroidism) characterized by orbital tissue inflammation, expansion, remodeling and fibrosis. Although the initiating trigger of GO is still indistinct, excessive orbital fibroblast activity is at the heart of its pathogenesis. Orbital fibroblasts are activated by cellular interactions with immune cells and the soluble factors they secrete. Orbital fibroblasts, especially from GO patients, express the thyrotropin receptor (TSH-receptor; TSHR), and activation of the orbital fibroblast population by stimulatory autoantibodies directed against the TSHR may provide an important link between GD and GO. Furthermore, stimulatory autoantibodies directed against the insulin-like growth factor-1 receptor have been proposed to contribute to orbital fibroblast activation in GO. Activated orbital fibroblasts produce inflammatory mediators thereby contributing to the orbital inflammatory process in GO. Moreover, orbital fibroblasts exhibit robust proliferative activity and extracellular matrix (especially hyaluronan) synthesizing capacity and can differentiate into adipocytes and myofibroblasts with disease progression, thereby contributing to tissue expansion/remodeling and fibrosis in GO. Orbital fibroblasts, especially those from GO patients, exhibit a hyper-responsive phenotype when compared to fibroblasts from other anatomical regions, which may further contribute to GO pathogenesis. Fibrocytes have been identified as additional source of orbital fibroblasts in GO, where they may contribute to orbital tissue inflammation, adipogenesis and remodeling/fibrosis. This review addresses our current view on the role that orbital fibroblasts fulfill in GO pathogenesis and both established as well as less established not fully crystallized concepts that need future studies will be discussed.
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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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    • "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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