Robust induction of PGHS-2 by IL-1 in orbital fibroblasts results from low levels of IL-1 receptor antagonist expression.

Human orbital fibroblasts are more susceptible to some actions of proinflammatory cytokines than are fibroblasts from other anatomic regions. These cells produce high levels of PGE(2) when activated by cytokines. Here we report that they express high levels of prostaglandin-endoperoxide H synthase (PGHS)-2, the inflammatory cyclooxygenase, when treated with IL-1beta. This induction results from enhanced PGHS-2 mRNA stability and small increases in gene promoter activity. The enhanced transcript stability is a result of actions of the cytokine on the 3'-untranslated region. Orbital fibroblasts, unlike those from skin, fail to express high levels of IL-1 receptor antagonist (IL-1ra) when treated with IL-1beta, leading to loss of modulation of IL-1 action. This can be overcome by transiently transfecting cells with IL-1ra. Thus a decreased level of IL-1ra expression in orbital fibroblasts may underlie the exaggerated responses to IL-1 observed in those cells and, therefore, the susceptibility of the orbit to inflammation.