Abstract
Human orbital fibroblasts exhibit a unique inflammatory phenotype. In the present study, we report that these fibroblasts, when treated with IL-1beta, express high levels of IL-6, a cytokine involved in B cell activation and the regulation of adipocyte metabolism. The magnitude of this induction is considerably greater than that in dermal fibroblasts and involves up-regulation of IL-6 mRNA levels. IL-1beta activates both p38 and ERK 1/2 components of the MAPK pathways. Disrupting these could attenuate the IL-6 induction. The up-regulation involves enhanced IL-6 gene promoter activity and retardation of IL-6 mRNA decay by IL-1beta. Dexamethasone completely blocked the effect of IL-1beta on IL-6 expression. Orbital fibroblasts also express higher levels of IL-6R than do skin-derived cells. When treated with rIL-6 (10 ng/ml), STAT3 is transiently phosphorylated. Thus, the exaggerated capacity of orbital fibroblasts to express high levels of both IL-6 and its receptor in an anatomic site-selective manner could represent an important basis for immune responses localized to the orbit in Graves' disease.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antigens, CD / biosynthesis
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Cell Movement / immunology
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Cells, Cultured
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Cytokine Receptor gp130
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Dexamethasone / pharmacology
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Fibroblasts / enzymology
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Fibroblasts / immunology*
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Fibroblasts / metabolism*
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Gene Expression Regulation / immunology
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Graves Disease / genetics
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Graves Disease / immunology*
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Graves Disease / pathology*
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Humans
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Immunophenotyping
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Interleukin-1 / physiology*
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / biosynthesis*
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Interleukin-6 / genetics
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MAP Kinase Signaling System / immunology
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Membrane Glycoproteins / biosynthesis
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Orbit / cytology*
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Orbit / immunology
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Orbit / metabolism
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Organ Specificity / immunology
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Promoter Regions, Genetic / immunology
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RNA, Messenger / biosynthesis
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Receptors, Interleukin-6 / biosynthesis
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Skin / cytology
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Skin / immunology
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Skin / metabolism
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Up-Regulation / genetics
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Up-Regulation / immunology
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p38 Mitogen-Activated Protein Kinases / physiology
Substances
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Antigens, CD
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IL6ST protein, human
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Interleukin-1
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Interleukin-6
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Membrane Glycoproteins
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RNA, Messenger
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Receptors, Interleukin-6
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Cytokine Receptor gp130
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Dexamethasone
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p38 Mitogen-Activated Protein Kinases