title: Evidence for PI3K-dependent CXCR3 agonist-induced degranulation of human cord blood-derived mast cells.
abstract: The chemokine receptor CXCR3, which has three known variants (CXCR3-A, CXCR3-B and CXCR3-Alt), has been implicated in the recruitment of mast cells to tissues in many different chronic diseases with its agonists found in elevated levels in several pulmonary diseases. All three variants of CXCR3 were detected in cord blood-derived mast cells at the mRNA level. Using an antibody that is unable to distinguish individual CXCR3 isoforms, we detected a marked down-regulation of intracellular protein during maturation from progenitor cells, with no concomitant changes in the modest surface expression of CXCR3. The known CXCR3 agonists CXCL9, CXCL10 and CXCL11 as well as the reported CXCR3-B agonist CXCL4, were able to induce Akt and ERK1/2 phosphorylation, as well as partial degranulation. Responses to all agonists were inhibited by pre-treatment with selective CXCR3 antagonists and pertussis toxin. Use of novel isoform-selective inhibitors, indicates that the p110 gamma isoform of PI3K is required for degranulation and signaling responses to CXCR3 agonists.
authors.affiliation: Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Willox
authors.forename: Irina
authors.initials: I
authors.lastname: Mirkina
authors.forename: John
authors.initials: J
authors.lastname: Westwick
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ward
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D015550:Cell Degranulation; D002454:Cell Differentiation; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D046529:Microscopy, Electron, Transmission; D010455:Peptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010978:Platelet Factor 4 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000819:agonists* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D017931:DNA Primers; D006023:Glycoproteins; D010455:Peptides; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D010978:Platelet Factor 4; D019869:Phosphatidylinositol 3-Kinases