Journal
MOLECULAR IMMUNOLOGY
Volume 45, Issue 1, Pages 65-75Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2007.05.009
Keywords
P2Y(2) receptor; VCAM-1; EGF receptor; metalloproteases; inflammation; sjogren's syndrome
Categories
Funding
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [R01DE007389] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [R01DE017591, K08DE017633] Funding Source: NIH RePORTER
- NIDCR NIH HHS [R01 DE007389, K08 DE017633, R01 DE017591, R01 DE07389-19, K08 DE017633-01, R01 DE017591-01, R01 DE007389-19] Funding Source: Medline
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Sjogren'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 P2Y(2) nucleotide receptor (P2Y(2)R) 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 P2Y(2)R 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 P2Y(2)R 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, P2Y(2)R 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 P2Y(2)R-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 P2Y(2)R 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. Published by Elsevier Ltd.
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