title: p38 MAPK regulates group IIa phospholipase A2 expression in interleukin-1beta -stimulated rat neonatal cardiomyocytes.
abstract: Group IIa phospholipase A(2) (GIIa PLA(2)) is released by some cells in response to interleukin-1beta. The purpose of this study was to determine whether interleukin-1beta would stimulate the synthesis and release of GIIa PLA(2) from cardiomyocytes, and to define the role of p38 MAPK and cytosolic PLA(2) in the regulation of this process. Whereas GIIa PLA(2) mRNA was not identified in untreated cells, exposure to interleukin-1beta resulted in the sustained expression of GIIa PLA(2) mRNA. Interleukin-1beta also stimulated a progressive increase in cellular and extracellular GIIa PLA(2) protein levels and increased extracellular PLA(2) activity 70-fold. In addition, interleukin-1beta stimulated the p38 MAPK-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2. Treatment with the p38 MAPK inhibitor, SB202190, decreased interleukin-1beta stimulated MAPKAP-K2 activity, GIIa PLA(2) mRNA expression, GIIa PLA(2) protein synthesis, and the release of extracellular PLA(2) activity. Infection with an adenovirus encoding a constitutively active form of MKK6, MKK6(Glu), which selectively phosphorylates p38 MAPK, induced cellular GIIa PLA(2) protein synthesis and the release of GIIa PLA(2) and increased extracellular PLA(2) activity 3-fold. In contrast, infection with an adenovirus encoding a phosphorylation-resistant MKK6, MKK6(A), did not result in GIIa PLA(2) protein synthesis or release by unstimulated cardiomyocytes. In addition, infection with an adenovirus encoding MKK6(A) abrogated GIIa PLA(2) protein synthesis and release by interleukin-1beta-stimulated cells. These results provide direct evidence that p38 MAPK activation was necessary for interleukin-1beta-induced synthesis and release of GIIa PLA(2) by cardiomyocytes.
authors.affiliation: Division of Vascular Surgery, Max Bell Research Center 1-917, Toronto General Hospital, Toronto, Ontario M5G-2C4, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Degousee
authors.forename: E
authors.initials: E
authors.lastname: Stefanski
authors.forename: T F
authors.initials: TF
authors.lastname: Lindsay
authors.forename: D A
authors.initials: DA
authors.lastname: Ford
authors.forename: R
authors.initials: R
authors.lastname: Shahani
authors.forename: C A
authors.initials: CA
authors.lastname: Andrews
authors.forename: D J
authors.initials: DJ
authors.lastname: Thuerauf
authors.forename: C C
authors.initials: CC
authors.lastname: Glembotski
authors.forename: T J
authors.initials: TJ
authors.lastname: Nevalainen
authors.forename: J
authors.initials: J
authors.lastname: Tischfield
authors.forename: B B
authors.initials: BB
authors.lastname: Rubin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006321:Heart / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D010741:Phospholipases A / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D054467:Phospholipases A2; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2