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)

Thrombin activates mast cells to release inflammatory mediators through a mechanism involving protease-activated receptor-1 (PAR-1). We hypothesized that PAR-1 activation would induce mast cell adhesion to fibronectin (FN). Fluorescent adhesion assay was performed in 96-well plates coated with FN (20 microg/ml). Murine bone marrow cultured mast cells (BMCMC) were used after 3-5 wk of culture (>98% mast cells by flow cytometry for c-Kit expression). Thrombin induced beta-hexosaminidase, IL-6, and matrix metalloproteinase-9 release from BMCMC. Thrombin and the PAR-1-activating peptide AparafluoroFRCyclohexylACitY-NH(2) (cit) induced BMCMC adhesion to FN in a dose-dependent fashion, while the PAR-1-inactive peptide FSLLRY-NH(2) had no effect. Thrombin and cit induced also BMCMC adhesion to laminin. Thrombin-mediated adhesion to FN was inhibited by anti-alpha(5) integrin Ab (51.1 +/- 6.7%; n = 5). The combination of anti-alpha(5) and anti-alpha(4) Abs induced higher inhibition (65.7 +/- 7.1%; n = 5). Unlike what is known for FcepsilonRI-mediated adhesion, PAR-1-mediated adhesion to FN did not increase mediator release. We then explored the signaling pathways involved in PAR-1-mediated mast cell adhesion. Thrombin and cit induced p44/42 and p38 phosphorylation. Pertussis toxin inhibited PAR-1-mediated BMCMC adhesion by 57.3 +/- 7.3% (n = 4), indicating that G(i) proteins are involved. Wortmannin and calphostin almost completely inhibited PAR-1-mediated mast cell adhesion, indicating that PI-3 kinase and protein kinase C are involved. Adhesion was partially inhibited by the mitogen-activated protein kinase kinase 1/2 inhibitor U0126 (24.5 +/- 3.3%; n = 3) and the p38 inhibitor SB203580 (25.1 +/- 10.4%; n = 3). The two inhibitors had additive effects. Therefore, thrombin mediates mast cell adhesion through the activation of G(i) proteins, phosphoinositol 3-kinase, protein kinase C, and mitogen-activated protein kinase pathways.
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PMID:Thrombin induces mast cell adhesion to fibronectin: evidence for involvement of protease-activated receptor-1. 1237 Mar 92

Immunoglobulin E (IgE) is important in mediating human allergic diseases. We tested the hypothesis that a human Ig Fc gamma-Fc epsilon bifunctional chimeric protein, GE2, would inhibit IgE class switch recombination (CSR) by co-aggregating B-cell CD32 and CD23. Indeed, GE2 directly inhibited epsilon germ-line transcription, subsequent CSR to epsilon and IgE protein production. This CSR inhibition was dependent on CD23 binding and the phosphorylation of extracellular signal-related kinase (ERK), and it was mediated via suppression of interleukin-4-induced STAT6 phosphorylation. Treatment with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase 1 (MAPKK1 (MEK1)) and MEK2 reversed the ability of GE2 to decrease CSR and STAT6 phosphorylation. GE2 stimulation induced ERK phosphorylation, whereas it did not alter the phosphorylation of c-Jun N-terminal kinase or p38 MAPK. The ability of GE2 to block human isotype switching to epsilon, in addition to its already demonstrated ability to inhibit mast cell and basophil function, suggests that it will provide an important novel benefit in the treatment of IgE-mediated diseases.
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PMID:Inhibition of interleukin-4-induced class switch recombination by a human immunoglobulin Fc gamma-Fc epsilon chimeric protein. 1280 27