Interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptor inhibit IL-1-induced glycosaminoglycan production in cultured human orbital fibroblasts from patients with Graves' ophthalmopathy.

Abstract

An accumulation of glycosaminoglycans (GAG) is a feature characteristic of orbital connective tissues from patients with Graves' ophthalmopathy (GO) that leads directly to the clinical expressions of the disease. Interleukin-1 (IL-1), produced by macrophages and fibroblasts within the diseased orbit, stimulates GAG synthesis by orbital fibroblasts. We designed the current study to determine whether particular agents might block this effect and thus be useful in the treatment of GO. Orbital fibroblast cultures were grown to confluence and incubated for 48 h with IL-1 (1-10 U/mL) alone or IL-1 (10 U/mL) in combination with IL-1 receptor antagonist (IL-1ra; 1-40 ng/mL) or soluble IL-1 receptor (sIL-1R; 0.25-10 micrograms/mL). Cells were labeled with [3H]glucosamine and processed for GAG quantitation. The addition of IL-1 alone stimulated GAG synthesis by 73-176% (mean, 104%; P < 0.05). Significant inhibition of IL-1-stimulated GAG synthesis was observed after treatment of normal fibroblasts with IL-1ra at a concentration of 5 ng/mL (12.5-fold molar excess; mean, 33%; P < 0.05); essentially complete inhibition was achieved at 40 ng/mL (100-fold molar excess; mean, 86%; P < 0.05). Significant inhibition of GAG synthesis by sIL-1R was observed at a concentration of 0.5 microgram/mL (720-fold molar excess; mean, 79%; P < 0.05), and inhibition was essentially complete at 1 microgram/mL (1440-fold molar excess; mean, 89%; P < 0.05). IL-1ra and sIL-1R are potent inhibitors of IL-1-induced GAG production by cultured human orbital fibroblasts. Our results suggest that these two compounds, shown in early trials to be safe when administered parenterally, may be useful in the prevention or treatment of GO.

Analysis of orbital T cells in thyroid-associated ophthalmopathy

“…Histological examination of RO tissue samples demonstrates mononuclear cell infiltration comprising mainly activated T cells, with a few B cells, macrophages and mast cells in patients with thyroidassociated ophthalmopathy (TAO) [3]. Cytokines released by activated immunocompetent cells stimulate RO fibroblasts to proliferate and to secrete glycosaminoglycans, leading to oedema and finally fibrosis [4][5][6][7]. Expression of intercellular adhesion molecule-1 (ICAM-1), HLA-DR and heat shock proteins (hsp) by orbital fibroblasts may also be induced by T cell-derived cytokines [8,9].…”

Radiotherapy for Graves’ disease. The possible role of low-dose radiotherapy

“…IL-1 receptor antagonist (IL-1RA) and soluble IL-1 receptor (sIL-1R) inhibit this GAG production. 35 l-selectin and ICAM-1 levels are elevated in patients with active GO. 36,37 ICAM-1 levels have been positively correlated with GO severity measured with the Total Eye Score or activity assessed by the CAS.…”

Novel Approaches to the Management of Graves` Ophthalmopathy

“…A few years ago Tan et al showed that both soluble IL-1 receptor antagonist (sIL-1RA), which binds to IL-1 receptor but does not activate it, and sIL-1R produced a dose-dependent inhibition of IL-1-induced glycosaminoglycan production in cultured orbital fibroblasts from GO 71 . IL-1RA was also shown to counteract IL-1 effects on human thyrocytes in culture 72 .…”