HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis.
The purpose of this study was to determine the effects of mast cell coculture on human orbital fibroblasts. Thyroid-associated ophthalmopathy is characterized by infiltration of lymphocytes and mast cells and connective tissue activation in the orbit, leading to a disordered accumulation of hyaluronan and intense inflammation. Here, we report that HMC-1, an established human mast cell line, can activate human orbital fibroblasts to produce increased levels of prostaglandin E2 (PGE2) and hyaluronan when cocultured. HMC-1 cells up-regulate, in these fibroblasts, the expression of PG endoperoxide H synthase-2 (EC 1.14.99.1, PGHS-2), the inflammatory cyclooxygenase. This induction, at a pretranslational level, underlies the increase in PGE2 synthesis. The up-regulation can be attenuated with dexamethasone (10 nM), and the increase in PGE2 production can be inhibited by SC 58125, a specific PGHS-2 inhibitor. Moreover, anti-interleukin-4 receptor antibodies can block prostanoid production in the fibroblasts elicited by HMC-1 cells, suggesting that this cytokine might represent a molecular conduit for mast cell/fibroblast cross-talk. HMC-1 cells also increased hyaluronan synthesis, as was evidenced by a 2-fold increase in [3H]glucosamine incorporation into the macromolecule. To our knowledge, these findings are the first demonstrating the ability of mast cells to activate orbital fibroblasts, and the findings suggest a potential role for these cell-cell interactions in the pathogenesis of thyroid-associated ophthalmopathy.
Smith
T J
TJ
Department of Medicine, Albany Medical College and Samuel S. Stratton Veterans Affairs Medical Center, New York 12208, USA.
Parikh
S J
SJ
D002460:Cell Line; D018920:Coculture Techniques; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D005123:Eye / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics*; D016695:Glycosyltransferases; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D007527:Isoenzymes / Q000235:genetics*; D008407:Mast Cells / Q000502:physiology*; D008565:Membrane Proteins; D009799:Ocular Physiological Phenomena; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D014166:Transferases; D029867:Xenopus Proteins
D007527:Isoenzymes; D008565:Membrane Proteins; D029867:Xenopus Proteins; D003907:Dexamethasone; D006820:Hyaluronic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D014166:Transferases; D016695:Glycosyltransferases; D014453:Glucuronosyltransferase; C056944:HAS1 protein, Xenopus; D000076002:Hyaluronan Synthases; D015232:Dinoprostone