Effect of Tumor Necrosis Factor-α, Interferon-γ, and Transforming Growth Factor-β on Adipogenesis and Expression of Thyrotropin Receptor in Human Orbital Preadipocyte Fibroblasts1

Graves' ophthalmopathy (GO) is an orbital autoimmune disease that is closely associated with Graves' hyperthyroidism. Examination of retroorbital tissues in GO reveals an accumulation of glycosaminoglycans, increased fat volume, lymphocytic infiltration, and the presence of several inflammatory cytokines. A subpopulation of human orbital fibroblasts can be differentiated in vitro into cells with the morphologic features of adipocytes. We demonstrated recently that these differentiated cultures show increased expression of functional TSH receptor (TSHr). To determine whether the presence of inflammatory cytokines might impact adipogenesis or TSHr expression in these cultures, we treated orbital fibroblasts from normal individuals or GO patients with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), or transforming growth factor-beta. We found that each of these cytokines inhibits TSH-dependent cAMP production and TSHr gene expression, and that TNF-alpha and IFN-gamma also inhibit morphological adipocyte differentiation. When cytokines were added after differentiation, the inhibition was less pronounced. Our results suggest that TNF-alpha, IFN-gamma, and transforming growth factor-beta may act within the orbit in GO to modulate expression of the putative orbital autoantigen, TSHr. In addition, the former two cytokines may play a role in determining the extent to which the volume of the orbital adipose tissue increases in this condition.