TY - JOUR
T1 - Evidence for PI3K-dependent CXCR3 agonist-induced degranulation of human cord blood-derived mast cells
AU - Willox, Ian
AU - Mirkina, Irina
AU - Westwick, John
AU - Ward, Stephen G
PY - 2010/8
Y1 - 2010/8
N2 - 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 p110γ isoform of PI3K is required for degranulation and signaling responses to CXCR3 agonists.
AB - 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 p110γ isoform of PI3K is required for degranulation and signaling responses to CXCR3 agonists.
UR - http://www.scopus.com/inward/record.url?scp=77955430014&partnerID=8YFLogxK
UR - http://dx.doi.org/10.1016/j.molimm.2010.05.005
U2 - 10.1016/j.molimm.2010.05.005
DO - 10.1016/j.molimm.2010.05.005
M3 - Article
SN - 0161-5890
VL - 47
SP - 2367
EP - 2377
JO - Molecular Immunology
JF - Molecular Immunology
IS - 14
ER -