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C. J. Hwang, N. Afifiyan, D. Sand, V. Naik, J. Said, S. Pollock, B. Chen, R. Phipps, T. Smith, R. Douglas; Orbital Fibroblasts From Patients With Thyroid-associated Ophthalmopathy Over-express Cd40: Cd154 Hyper-induces Il-6, Il-8 And Mcp-1. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1537.
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Fibroblast diversity represents an emerging concept critical to our understanding of tissue inflammation, repair and remodeling. Orbital fibroblasts heterogeneously display Thy-1 and exhibit unique phenotypic attributes that may explain the susceptibility of the human orbit to thyroid-associated ophthalmopathy (TAO). In the current study we investigate the role of CD40 ligation upon macrophage chemoattractant protein -1 (MCP-1), IL-6 and IL-8 expression in fibroblasts from patients with TAO.
Human orbital fibroblasts were cultured from tissues obtained with informed consent from patients with TAO and from patients undergoing surgery for other, non-inflammatory conditions. The fibroblasts were then examined by flow cytometry, microscopy, and cytokine assays.
We report that orbital fibroblasts from patients with TAO express elevated levels of CD40. Surface CD40 can be further up-regulated by interferon γ (IFN-γ) in both TAO and control fibroblasts. This up-regulation is mediated through Jak2 and can be blocked by dexamethasone and AG490, a powerful and specific inhibitor of the tyrosine kinase. Treatment with CD154, the ligand for CD40, up-regulates the expression of IL-6, IL-8 and MCP-1 in TAO fibroblasts, but fails to do so in control cultures. Thy-1+ fibroblasts displayed higher CD40 levels than do their Thy-1- counterparts and are largely responsible for this cytokine production. IL-1β also induces MCP-1, IL-6 and IL-8 more vigorously in TAO-derived fibroblasts.
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