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

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.

Transformujący czynnik wzrostu β1 (TGFβ1) i naczyniowo-śródbłonkowy czynnik wzrostu (VEGF) we krwi ludzi zdrowych i chorych z orbitopatią Gravesa — nowy mechanizm działania glikokortykosteroidów?

“…Enlargement of orbital tissue mass occurs through the accumulation of extracellular matrix (ECM), scar-forming myofibroblasts, and/or fat [34,42,46,49]. TGFb1 is synthesised primarily by platelets, macrophages/monocytes, lymphocytes, fibroblasts, and epithelial cells [50].…”

Electrophilic Peroxisome Proliferator–Activated Receptor-γ Ligands Have Potent Antifibrotic Effects in Human Lung Fibroblasts

“…RNA (1.0 mg) was incubated with PCR buffer, 0.5 mg of oligo (dT) [12][13][14][15][16][17][18] primer (Invitrogen), 10 mM deoxynucleotide-triphosphate (dNTP) for 10 minutes at 708C and 5 minutes in ice water, followed by addition of 40 U of recombinant RNasin RNase inhibitor (Promega, Madison, WI), 0.1 mM DTT, and 200 U of Superscript III reverse transcriptase (RT; Invitrogen). The mixture was further incubated for 5 minutes at room temperature, 60 minutes at 508C, and 15 minutes at 708C.…”

“…After ligand binding, PPARg heterodimerizes with the retinoid X receptor (RXR), and is translocated to the nucleus, where it binds to PPARg response elements (PPREs) (14,17). PPARg agonists regulate fat metabolism and adipogenesis (18). Endogenous PPARg ligands include prostaglandin 15-deoxy-D 12,14 -prostaglandin J 2 (15 d-PGJ 2 ), as well as lysophosphatidic acid and 15S-hydroxyeicosatetraenoic acid.…”

Role of bioactive lipid mediators in obese adipose tissue inflammation and endocrine dysfunction

“…In addition, a significant downregulation in the expression and secretion of the proinflammatory adipokine leptin has been reported in adipocytes exposed to exogenous 15d-PGJ 2 (Sinha et al, 1999). Importantly, 15d-PGJ 2 stimulates adipogenesis (Sinha et al, 1999) and also exerts proadipogenic actions in fibroblasts, although in this case lymphocytes are the source of this cyclopentenone PG (Feldon et al, 2006). Surprisingly, an impaired adipogenic program has been identified in 3T3-L1 cells with stable transfection of PGD synthase and appreciably higher levels of endogenous PGD 2 -derived metabolites, suggesting a complex regulatory interaction between PPARg and pro-adipogenic lipid mediators (Hossain et al, 2012).…”