title: Leukoregulin upregulation of prostaglandin endoperoxide H synthase-2 expression in human orbital fibroblasts.
abstract: Human orbital fibroblasts from patients with severe thyroid-associated ophthalmopathy are particularly susceptible to the actions of a variety of proinflammatory molecules. In this study, we demonstrate that the inductions of prostaglandin endoperoxide H synthase-2 (PGHS-2), interleukin (IL)-1alpha, and IL-1beta by leukoregulin, a product of activated T lymphocytes, are far more robust in orbital fibroblasts than those observed in dermal fibroblasts. These actions of leukoregulin are mediated through an intermediate induction of IL-1alpha. In contrast, leukoregulin also induces IL-1-receptor antagonist (IL-1ra) expression in orbital fibroblasts, but this induction is considerably greater in dermal fibroblasts (2.3- vs. 8.5-fold). Interrupting the effects of IL-1alpha, either with a neutralizing antibody or with exogenous IL-1ra, can block the induction of PGHS-2 by leukoregulin. Leukoregulin increases PGHS-2 gene transcription in orbital fibroblasts but exerts the major effect on cyclooxygenase expression by enhancing the stability of mature PGHS-2 mRNA. The cytokine triggers nuclear translocation of nuclear factor-kappaB (NF-kappaB) p50/p50 homodimers and p50/p65 heterodimers, and an inhibitor of this transcriptional factor, pyrrolidinedithiocarbamate, 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 observed in orbital and dermal fibroblasts. NF-kappaB plays an important role in mediating the effects of leukoregulin on PGHS-2 expression.
authors.affiliation: Division of Molecular and Cellular Medicine, Departments of Medicine and Biochemistry and Molecular Biology, Albany Medical College and Samuel S. Stratton Veterans Affairs Medical Center, Albany, New York 12208, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Cao
authors.forename: T J
authors.initials: TJ
authors.lastname: Smith
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D020405:Dermis / Q000166:cytology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D006111:Graves Disease / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics*; D008222:Lymphokines / Q000494:pharmacology*; D008565:Membrane Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009500:Neutralization Tests; D009915:Orbit / Q000166:cytology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012795:Sialoglycoproteins / Q000276:immunology / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000906:Antibodies; D018931:Antineoplastic Agents, Hormonal; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C044162:leukoregulin; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone