Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 45, Issue 8, Pages 1657-1668Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2013.05.006
Keywords
Cyclooxygenase-2; Cytosolic phospholipase A(2); Inflammation; Lung injury; Transcription factor
Categories
Funding
- National Science Council, Taiwan [NSC101 -2314-B-182A-112, NSC98-2321-B-182-004, NSC99-2321-B-182-003, NSC98-2314-B-182-021-MY3]
- Ministry of Education, Taiwan [EMRPD1B0311, EMRPD1B0321]
- Chang Gung Medical Research Foundation, Taiwan [CMRPG391032, CMRPG381522, CMRPD180373, CMRPD1A0151, CMRPD1B0381, CMRPG3B1091]
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Up-regulation of cyclooxygenase (COX)-2 and prostaglandin E-2 (PGE(2)) are implicated in lung inflammation. Adenosine 5'-triphosphate (ATP) has been shown to act via activation of P2 purinoceptors, leading to COX-2 expression in various inflammatory diseases. The mechanisms of ATP-induced COX-2 expression and PGE(2) release remain unclear. We showed that pretreatment with the inhibitors of P2 receptors (PPADS and Suramin), Gq protein (GPA2A), phosphatidylcholine-phospholipase C (PC-PLC; D609), phosphoinositide-phospholipase C (PI-PLC; ET-18-OCH3), Ca2+/calmodulin-dependent protein kinase II (CaMKII; KN62), protein kinase C (PKC; G66976, Ro-318220, GF109203X, and rottlerin), MEK1/2 (PD98059), p38 MAPK (SB202190), and nuclear factor-kappaB (NE-kappa B; Bay11-7082) and the intracellular calcium chelator (BAPTA/AM) or transfection with siRNAs of these molecules and cPLA2 reduced ATP gamma S-induced COX-2 expression or PGE2 production in A549 cells. In addition, ATP gamma S-induced elevation of intracellular Ca2+ concentration was attenuated by PPADS, Suramin, D609, or ET-18-00-13. ATP-1Sinduced p38 MAPK, p42/p44 MAPK, and NE-KB p65 activation were inhibited by Go6976, Ro-318220, GF109203X, or rottlerin. AM'S also induced cPLA(2) phosphorylation and activity, which were reduced via inhibition of P2 receptors, PKCs, p38 MAPK, and p42/p44 MAPK. ATPyS-induced cPLA2 expression was inhibited by SB202190, PD98059, or Bayll-7082. In the in vitro study, we established that ATID gamma S induced PGE2 generation via a cPLA(2)/COX-2-dependent pathway. In the in vivo study, we found that ATP gamma S induced COX-2 mRNA expression in the lungs and leukocyte (mainly eosinophils and neutrophils) count in bronchoalveolar lavage (BAL) fluid in mice via a P2 receptors-dependent signaling pathway. We concluded that ATPyS may induce lung inflammation via a cPLA(2)/COX-2/PGE(2)-dependent pathway. (C) 2013 Elsevier Ltd. All rights reserved.
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