MODULATION OF GRAVES ORBITAL FIBROBLAST PROLIFERATION BY CYTOKINES AND GLUCOCORTICOID RECEPTOR AGONISTS

Purpose. Paracrine/autocrine interactions between orbital fibroblasts (OF) and infiltrating lymphocytes/macrophages are thought to play a ce ntral role in the evolution of Graves' ophthalmopathy (GO). Compounds capable of stimulating the proliferation and synthetic capacities of O F may be of particular importance to these processes, because fibrobla sts are known to both produce and respond to certain paracrine factors . Methods. The effects of interleukin-1 alpha, interleukin-2, interleu kin-4, interleukin-6, insulin-like growth factor I, transforming growt h factor beta, and platelet-derived growth factor on OF monolayers der ived from orbital fatty connective tissue and extraocular muscle endom ysium of atients with severe GO undergoing orbital decompression (n = 3), and from connective tissue of normal persons (n = 3) were investig ated. Stimulation of proliferation in growth-arrested OF was determine d using immunocytochemical staining for the cell-proliferation-related nuclear antigen recognized by a monoclonal anti-Ki 67 antibody. In ad dition, the effects of OF coincubation with one of the aforementioned compounds and hydrocortisone (10(-7) M), the selective glucocorticoid receptor agonist RU 28362 (10(-7) M), or the glucocorticoid receptor a ntagonist RU 38486 (10(-7) M) were assessed. Results. Under baseline c onditions (0.1% fetal bovine serum), the proportion of proliferating c ells was significantly higher in GO-OF compared with normal OF (p < 0. 001). Significant stimulation of GO-OF proliferation was observed with interleukin-1 alpha (10 U/ml), interleukin-4 (1 ng/ml), insulin-like growth factor I (10 ng/ml), transforming growth factor beta (10 ng/ml) , platelet-derived growth factor (1 ng/ml), and 1% or 15% fetal bovine serum (all P < 0.01), but not with interleukin-2 (10 U/ml) and interl eukin-6 (100 U/ml). Compared with GO-OF, proliferation of normal OF wa s stimulated by fetal bovine serum to a similar degree, by interleukin -4, insulin-like growth factor I, transforming growth factor beta, and platelet-derived growth factor to a significantly lesser degree (all P < 0.01), and was unaffected by interleukin-1 alpha, interleukin-2, a nd interleukin-6. Compared with normal OF, either glucocorticoid recep tor agonists, but not testosterone or progesterone, specifically inhib ited the cytokine-stimulated proliferation of GO-OF to a significantly greater degree (P < 0.01). Conclusions. The enhanced proliferative ca pacity of GO-OF at baseline and in response to certain cytokines could play a role in the evolution of the clinical manifestations in GO. In hibition of cytokine-activated cellular functions may be one mechanism by which glucocorticosteroids exert clinically useful effects in GO.