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(American Journal of Pathology. 2006;169:1183-1193.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060434

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

Steven E. Feldon*, Charles W. O’Loughlin*{dagger}, Denise M. Ray{dagger}, Shira Landskroner-Eiger*{dagger}, Kathryn E. Seweryniak{dagger} and Richard P. Phipps*{dagger}

From the Departments of Ophthalmology* and Environmental Medicine and the Lung Biology and Disease Program,{dagger} University of Rochester School of Medicine and Dentistry, Rochester, New York

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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