Abstract
Thyroid eye disease is characterized by the infiltration of leukocytes and accumulation of hyaluronan (HA) in orbital tissue. Inflamed orbital tissue expands in size due to excessive HA and to the formation of scar tissue (fibrosis) and/or adipose accumulation. Transforming growth factor β (TGF-β) acts as a key inducer of fibrosis by enhancing extracellular matrix production. Treatment of primary human orbital fibroblasts with TGF-β led to significant increases in both HA synthesis and secretion. TGF-β also strongly induced hyaluronan synthase 1 (HAS1) and HAS2 mRNA levels, which increased 50- and 6-fold, respectively. Remarkably, the addition of the peroxisome proliferator-activated receptor (PPARγ) ligands pioglitazone (Pio) or rosiglitazone (Rosi) to TGF-β-treated orbital fibroblasts attenuated HA synthesis and reduced HAS1 and HAS2 mRNA levels. The attenuation of TGF-β function by Pio and Rosi was independent of PPARγ activity. Furthermore, Pio and Rosi treatment inhibited TGF-β-induced T cell adhesion to orbital fibroblasts. Our findings demonstrate that TGF-β plays an important role in HA synthesis and in the inflammatory response by enhancing or facilitating inflammatory cell infiltration and adhesion to orbital tissue. Pio and Rosi exhibit anti-fibrotic and anti-inflammatory activity and may be useful in treating thyroid eye disease.