title: Potentiation of protein kinase C zeta activity by 15-deoxy-delta(12,14)-prostaglandin J(2) induces an imbalance between mitogen-activated protein kinases and NF-kappa B that promotes apoptosis in macrophages.
abstract: Activation of the macrophage cell line RAW 264.7 with lipopolysaccharide (LPS) transiently activates protein kinase C zeta (PKC zeta) and Jun N-terminal kinase (JNK) through a phosphoinositide-3-kinase (PI3-kinase)-dependent pathway. Incubation of LPS-treated cells with the cyclopentenone 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) promoted a sustained activation of PKC zeta and JNK and inhibited I kappa B kinase (IKK) and NF-kappa B activity. Accordingly, 15dPGJ(2) induced an imbalance between JNK and IKK activities by increasing the former signaling pathway and inhibiting the latter signaling pathway. Under these conditions, apoptosis was significantly enhanced; this response was very dependent on PKC zeta and JNK activation. The effect of 15dPGJ(2) on PKC zeta activity observed in LPS-activated macrophages was not dependent on a direct action of this prostaglandin on the enzyme but was due to the activation of a step upstream of PI3-kinase. Moreover, LPS promoted the redistribution of activated PKC zeta from the cytosol to the nucleus, a process that was enhanced by treatment of the cells with 15dPGJ(2) that favored a persistent and broader distribution of PKC zeta in the nucleus. These results indicate that 15dPGJ(2) and other cyclopentenone prostaglandins, through the sustained activation of PKC zeta, might contribute significantly to the process of resolution of inflammation by promoting apoptosis of activated macrophages.
authors.affiliation: Instituto de Bioquímica, Centro Mixto CSIC-UCM, Facultad de Farmacia, and Centro Nacional de Investigaciones Cardiovasculares, 28040 Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Castrillo
authors.forename: Paqui G
authors.initials: PG
authors.lastname: Través
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.forename: Scott
authors.initials: S
authors.lastname: Parkinson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Parker
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D051550:I-kappa B Kinase; D007155:Immunologic Factors / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D051550:I-kappa B Kinase; D007155:Immunologic Factors; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D015230:Prostaglandin D2; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C081975:protein kinase C eta; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse