IL-1 beta induces IL-6 expression in human orbital fibroblasts: identification of an anatomic-site specific phenotypic attribute relevant to thyroid-associated ophthalmopathy.
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.
Division of Molecular Medicine, Department of Medicine, Harbor-University of California at Los Angeles, Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
Beiling
B
Chen
Shanli
S
Tsui
Terry J
TJ
Smith
D015703:Antigens, CD / Q000096:biosynthesis; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006111:Graves Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D007375:Interleukin-1 / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009915:Orbit / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D009928:Organ Specificity / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D050822:Cytokine Receptor gp130; D003907:Dexamethasone; D007375:Interleukin-1; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C494199:IL6ST protein, human