Potentiation of protein kinase C ζ activity by 15-Deoxy-Δ12,14-prostaglandin J2 induces an imbalance between mitogen-activated protein kinases and NF-κB that promotes apoptosis in acrophages

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 J2 (15dPGJ2) promoted a sustained activation of PKC{zeta} and JNK and inhibited I{kappa}B kinase (IKK) and NF-{kappa}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{zeta} and JNK activation. The effect of 15dPGJ2 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 15dPGJ2 that favored a persistent and broader distribution of PKC{zeta} in the nucleus. These results indicate that 15dPGJ2 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.