Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes.
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.
Feldon
Steven E
SE
Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA.
O'loughlin
Charles W
CW
Ray
Denise M
DM
Landskroner-Eiger
Shira
S
Seweryniak
Kathryn E
KE
Phipps
Richard P
RP
D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis; D002454:Cell Differentiation; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006111:Graves Disease / Q000201:enzymology; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism*; D009915:Orbit / Q000166:cytology*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D008024:Ligands; D008565:Membrane Proteins; D047495:PPAR gamma; D011453:Prostaglandins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015230:Prostaglandin D2