Lung inflammation caused by adenosine-5'-triphosphate is mediatedvia Ca2+/PKCs-dependent COX-2/PGE2induction

I-Ta Leea, Chih Chung Lin, Wei Ning Lin, Wan Ling Wu, Li Der Hsiao, Chuen Mao Yang

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Up-regulation of cyclooxygenase (COX)-2 and prostaglandin E 2(PGE2) are implicated in lung inflam-mation. 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-2expression and PGE2 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; Gö6976, Ro-318220, GF109203X, and rottlerin), MEK1/2(PD98059), p38 MAPK (SB202190), and nuclear factor-kappaB (NF- κB; Bay11-7082) and the intracel-lular calcium chelator (BAPTA/AM) or transfection with siRNAs of these molecules and cPLA2 reduced ATPγS-induced COX-2 expression or PGE2production in A549 cells. In addition, ATPγS-induced elevation of intracellular Ca2+concentration was attenuated by PPADS, Suramin, D609, or ET-18-OCH3. ATPγS-induced p38 MAPK, p42/p44 MAPK, and NF- κB p65 activation were inhibited by Gö6976, Ro-318220,GF109203X, or rottlerin. ATPγS also induced cPLA2 phosphorylation and activity, which were reduced via inhibition of P2 receptors, PKCs, p38 MAPK, and p42/p44 MAPK. ATPγS-induced cPLA 2 expression was inhibited by SB202190, PD98059, or Bay11-7082. In the in vitro study, we established that ATPγSinduced PGE2 generation via a cPLA2/COX-2-dependent pathway. In the in vivo study, we found that ATPγS 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 ATPγS may induce lung inflammation via a cPLA2/COX-2/ PGE2-dependent pathway.

Original languageEnglish
Pages (from-to)1657-1668
Number of pages12
JournalInternational Journal of Biochemistry and Cell Biology
Volume45
Issue number8
DOIs
Publication statusPublished - Jan 1 2013
Externally publishedYes

Keywords

  • Cyclooxygenase-2
  • Inflammation
  • Lung injury
  • Transcription factor

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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