Introduction: Anti-cytokine therapy may be useful for the treatment of active thyroid associated ophthalmopathy (TAO). We aimed to establish the effects of selected cytokines on intercellular adhesion molecule 1 (ICAM1) expression and adipogenesis in orbital fibroblasts (OFs) from patients with and without TAO.
Methods: Orbital tissue was taken during surgery from 5 patients with TAO and 5 control subjects. Primary cultures of OFs were established and stained for ICAM1 expression by flow cytometry. OFs were exposed to cytokines (TNFα, IL1, IFNγ, IL10 and TGFβ) and/or anti-cytokine agents (adalimumab, etanercept, infliximab and anakinra) and grown for 48 hours. The concentrations of anti-cytokine agents used were in the range of peak serum levels after therapeutic administration and also 1/100 of peak concentration. OFs were also cultured in adipogenic media in the presence of TNFα or IL1+/− their antagonists for 10 days, and adipogenesis measured by staining and extraction of oil-red-O, and by visual assessment.
Results: TNFα, IL1 and IFNγ (0.1 ng/ml) stimulated ICAM1 expression 8 to 10 fold in OFs from patients with TAO. Interleukin 10 (10 ng/ml) and TGFβ (1 ng/ml) had no effect. Similar responses were seen in OFs from control subjects. Anti-cytokine agents inhibited the ICAM1 responses to 0.1 ng/ml of TNFα or IL1 by 84% to 92% using peak concentrations and by 60% to 88% using 1/100 of peak concentrations (P values <0.01). IL1 stimulated adipogensesis (+42% and +400%) whilst TNFα inhibited adipogenesis (−41% and −100%), as measured by oil-red-O extraction and visual scoring, respectively (P values <0.05).
Conclusion: TNFα and IL1 have stimulatory effects on ICAM1 expression, but opposite effects on adipogenesis in orbital fibroblasts in vitro. Anti-TNFα agents have the potential to worsen TAO, particularly in patients where adipogenesis is prominent. Anti-IL1 agents may be the anti-cytokine agent of choice for clinical trials in active TAO.
01 - 05 Apr 2006
European Society of Endocrinology