Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis. 1043 7

Thyroid eye disease (TED) is a debilitating disorder characterized by the accumulation of adipocytes and hyaluronan (HA). Production of HA by fibroblasts leads to remarkable increases in tissue volume and to the anterior displacement of the eyes. Prostaglandin D(2) (PGD(2)), mainly produced by mast cells, promotes orbital fibroblast adipogenesis. The mechanism by which PGD(2) influences orbital fibroblasts and their synthesis of HA is poorly understood. We report here that mast cell-derived PGD(2) is a key factor that promotes HA biosynthesis by orbital fibroblasts. Primary orbital fibroblasts from TED patients were isolated and used to test the effects of PGD(2), prostaglandin J(2), as well as prostaglandin D receptor (DP) agonists and antagonists on HA synthesis. The expression of HA synthase (HAS), hyaluronidase, DP1, and DP2 mRNA levels was assessed by PCR. Small interfering RNAs against HAS1 or HAS2 were used to assess the importance of HAS isoforms on HA production. Treatment of human orbital fibroblasts with PGD(2) and PGJ(2) increased HA synthesis and HAS mRNA. HAS2 was the dominant isoform responsible for HA production by PGD(2). The effect of PGD(2) on HA production was mimicked by the selective DP1 agonist BW245C. The DP1 antagonist MK-0524 completely blocked PGD(2)-induced HA synthesis. Human mast cells (HMC-1) produced PGD(2). Co-culture of HMC-1 cells with orbital fibroblasts induced HA production and inhibition of mast cell-derived PGD(2) prevented HA synthesis. Mast cell-derived PGD(2) increased HA production via activation of DP1. Selectively targeting the production of PGD(2) and/or activation of DP1 may prevent pathological changes associated with TED.
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PMID:Mast cell-derived prostaglandin D2 controls hyaluronan synthesis in human orbital fibroblasts via DP1 activation: implications for thyroid eye disease. 2030 56