P2Y2 nucleotide receptor activation up-regulates vascular cell adhesion molecule-1 [corrected] expression and enhances lymphocyte adherence to a human submandibular gland cell line.
Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease that causes salivary and lacrimal gland tissue destruction resulting in impaired secretory function. Although lymphocytic infiltration of salivary epithelium is associated with SS, the mechanisms involved have not been adequately elucidated. Our previous studies have shown that the G protein-coupled P2Y2 nucleotide receptor (P2Y2R) is up-regulated in response to damage or stress of salivary gland epithelium, and in salivary glands of the NOD.B10 mouse model of SS-like autoimmune exocrinopathy. Additionally, we have shown that P2Y2R activation up-regulates vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells leading to the binding of monocytes. The present study demonstrates that activation of the P2Y2R in dispersed cell aggregates from rat submandibular gland (SMG) and in human submandibular gland ductal cells (HSG) up-regulates the expression of VCAM-1. Furthermore, P2Y2R activation mediated the up-regulation of VCAM-1 expression in HSG cells leading to increased adherence of lymphocytic cells. Inhibitors of EGFR phosphorylation and metalloprotease activity abolished P2Y2R-mediated VCAM-1 expression and decreased lymphocyte binding to HSG cells. Moreover, silencing of EGFR expression abolished UTP-induced VCAM-1 up-regulation in HSG cells. These results suggest that P2Y2R activation in salivary gland cells increases the EGFR-dependent expression of VCAM-1 and the binding of lymphocytes, a pathway relevant to inflammation associated with SS.
Baker
Olga J
OJ
Department of Biochemistry, University of Missouri-Columbia, 540E Christopher S. Bond Life Sciences Center, 1201 Rollins Road, Columbia, MO 65211-0001, USA.
Camden
Jean M
JM
Rome
Danny E
DE
Seye
Cheikh I
CI
Weisman
Gary A
GA
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D045726:Metalloproteases / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D013363:Submandibular Gland / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D014544:Uridine Triphosphate / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*; D019061:src-Family Kinases / Q000378:metabolism
C546385:P2RY2 protein, human; C546386:P2ry2 protein, mouse; C546387:P2ry2 protein, rat; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D019010:Vascular Cell Adhesion Molecule-1; D066246:ErbB Receptors; D019061:src-Family Kinases; D045726:Metalloproteases; D014544:Uridine Triphosphate