Potentiation of Protein Kinase C ζ Activity by 15-Deoxy-Δ 12,14 -Prostaglandin J 2 Induces an Imbalance between Mitogen-Activated Protein Kinases and NF-κB That Promotes Apoptosis in Macrophages

Abstract

ABSTRACT Activation of the macrophage cell line RAW 264.7 with lipopolysaccharide (LPS) transiently activates protein kinase C ζ (PKCζ) 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-Δ 12,14 -prostaglandin J 2 (15dPGJ 2 ) promoted a sustained activation of PKCζ and JNK and inhibited IκB kinase (IKK) and NF-κB 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 PKCζ and JNK activation. The effect of 15dPGJ 2 on PKCζ 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 PKCζ 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 PKCζ in the nucleus. These results indicate that 15dPGJ 2 and other cyclopentenone prostaglandins, through the sustained activation of PKCζ, might contribute significantly to the process of resolution of inflammation by promoting apoptosis of activated macrophages.