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Molecular and Cellular Biology, February 2003, p. 1196-1208, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1196-1208.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Potentiation of Protein Kinase C Activity by 15-Deoxy-^12,14-Prostaglandin J₂ Induces an Imbalance between Mitogen-Activated Protein Kinases and NF-B That Promotes Apoptosis in Macrophages

Antonio Castrillo,^1, Paqui G. Través,¹ Paloma Martín-Sanz,¹ Scott Parkinson,² Peter J. Parker,² and Lisardo Boscá^1*

Instituto de Bioquímica (Centro Mixto CSIC-UCM), Facultad de Farmacia, and Centro Nacional de Investigaciones Cardiovasculares, 28040 Madrid, Spain,¹ Protein Phosphorylation Laboratory, Cancer Research UK Lincoln's Inn Fields Laboratories, London WC2A 3PX, United Kingdom²

Received 8 May 2002/ Returned for modification 4 June 2002/ Accepted 21 November 2002

Activation of the macrophage cell line RAW 264.7 with lipopolysaccharide (LPS) transiently activates protein kinase C (PKC) 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-^12,14-prostaglandin J₂ (15dPGJ₂) promoted a sustained activation of PKC and JNK and inhibited IB kinase (IKK) and NF-B activity. Accordingly, 15dPGJ₂ 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 and JNK activation. The effect of 15dPGJ₂ on PKC 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 from the cytosol to the nucleus, a process that was enhanced by treatment of the cells with 15dPGJ₂ that favored a persistent and broader distribution of PKC in the nucleus. These results indicate that 15dPGJ₂ and other cyclopentenone prostaglandins, through the sustained activation of PKC, might contribute significantly to the process of resolution of inflammation by promoting apoptosis of activated macrophages.

Present address: Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095-1662.

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