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 PGE₂when 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-1β. 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-1β, 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.