Leukoregulin upregulation of prostaglandin endoperoxide H synthase-2 expression in human orbital fibroblasts

Human orbital fibroblasts from patients with severe thyroid-associated opht halmopathy are particularly susceptible to the actions of a variety of proi nflammatory molecules. In this study, we demonstrate that the inductions of prostaglandin endoperoxide H synthase-2 (PGHS-2), interleukin (IL)-1 alpha , and IL-1 beta by leukoregulin, a product of activated T lymphocytes, are far more robust in orbital fibroblasts than those observed in dermal fibrob lasts. These actions of leukoregulin are mediated through an intermediate i nduction of IL-1 alpha. In contrast, leukoregulin also induces IL-1-recepto r antagonist (IL-1ra) expression in orbital fibroblasts, but this induction is considerably greater in dermal fibroblasts (2.3- vs. 8.5-fold). Interru pting the effects of IL-1 alpha, either with a neutralizing antibody or wit h exogenous IL-1ra, can block the induction of PGHS-2 by leukoregulin. Leuk oregulin increases PGHS-2 gene transcription in orbital fibroblasts but exe rts the major effect on cyclooxygenase expression by enhancing the stabilit y of mature PGHS-2 mRNA. The cytokine triggers nuclear translocation of nuc lear factor-kappa B (NF-kappa B) p50/p50 homodimers and p50/p65 heterodimer s, and an inhibitor of this transcriptional factor, pyrrolidinedithiocarbam ate, can attenuate the PGHS-2 induction. Thus differential inducibility of the members of the IL-1 family of genes in orbital fibroblasts would appear to underlie, at least in part, the differences in PGHS-2 induction observe d in orbital and dermal fibroblasts. NF-kappa B plays an important role in mediating the effects of leukoregulin on PGHS-2 expression.