IL‐1 Induces Lower sIL‐1ra and Higher icIL‐1ra IL‐1ra Protein Expression in Orbital vs. Dermal Fibroblasts

Abstract

Thyroid ophthalmopathy is an autoimmune disorder of orbital connective tissue associated with Graves’ disease. It is characterized by severe inflammation and extensive tissue remodeling. We have reported previously that orbital fibroblasts exhibit exaggerated responses to IL-1 and that the basis for this is a diminished production of IL-1ra, which usually modulates IL-1 action. Here we investigate the profile of IL-1ra isoforms expressed in orbital vs. dermal fibroblasts. sIL-1ra protein released from orbital fibroblasts in response to IL-1β was considerably lower than dermal fibroblasts. In contrast, icIL-1ra protein associated with cell lysates was substantially greater in orbital fibroblasts. Steady-state mRNA levels in IL-1 treated fibroblasts revealed a divergent pattern. In orbital fibroblasts, IL-1β induced sIL-1ra mRNA in a time-dependent manner, but in dermal fibroblasts, levels were invariant. IL-1β induced sIL-1ra mRNA in dermal fibroblasts, but levels were uninfluenced in orbital cultures. Unspliced sIL-1ra levels were constantly high in orbit and unaffected by IL-1β treatment. In dermal cells, basal unspliced sIL-1ra mRNA levels were undetectable and IL-1β induced this transcript. Conclusion these results indicate cell-specific regulation of IL-1ra expression. This could represent the molecular basis for exaggerated responses to IL-1β in orbital connective tissue and susceptibility of the orbit to autoimmune diseases. This work was supported in part by the National Institutes of Health Grants EY008976, EY011708, and DK063121.