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^*, Denise M. Ray, Shira Landskroner-Eiger^*, Kathryn E. Seweryniak and Richard P. Phipps^*

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

The differentiation of preadipocyte fibroblasts to adipocytesis 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 infiltratedwith T lymphocytes as part of the autoimmune process. The orbitalfibroblasts convert to fat-like cells causing the eye to protrude,which is disfiguring and can lead to blindness. Recently, thetranscription 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 vitrodifferentiation of preadipocyte fibroblasts to adipocytes. Weshow herein several novel findings. First, that activated Tlymphocytes from Graves’ patients drive the differentiationof PPAR- ${gamma}$ -expressing orbital fibroblasts to adipocytes. Second,this adipogenic differentiation is blocked by nonselective smallmolecule cyclooxygenase (Cox)-1/Cox-2 inhibitors and by Cox-2selective inhibitors. Third, activated, but not naïve,human T cells highly express Cox-2 and synthesize prostaglandinD₂ and related prostaglandins that are PPAR- ${gamma}$ ligands. Theseprovocative new findings provide evidence for how activatedT lymphocytes, through production of PPAR- ${gamma}$ ligands, profoundlyinfluence human fibroblast differentiation to adipocytes. Theyalso suggest the possibility that, in addition to the orbit,T lymphocytes influence the deposition of fat in other tissues.