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J. Biol. Chem., Vol. 276, Issue 32, 30527-30536, August 10, 2001

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Functional Coupling between Secretory and Cytosolic Phospholipase A₂ Modulates Tumor Necrosis Factor-- and Interleukin-1-induced NF-B Activation^*

Marit W. Anthonsen, Anita Solhaug, and Berit Johansen

From the UNIGEN Center for Molecular Biology, Faculty of Chemistry and Biology, Norwegian University of Science and Technology, N-7489 Trondheim, Norway

Tumor necrosis factor (TNF)- and interleukin (IL)-1 are potent activators of the transcription factor NF-B, induced during inflammatory conditions. We have previously shown that both secretory and cytosolic phospholipase A₂ (PLA₂) are involved in TNF-- and IL-1-induced NF-B activation. In this study, we have addressed the mechanism of PLA₂ involvement with respect to downstream arachidonic acid (AA) metabolites and the functional coupling between PLA₂s mediating NF-B activation. We show that in addition to inhibitors of secretory and cytosolic PLA₂s, 5-lipoxygenase inhibitors attenuate TNF-- and IL-1-stimulated NF-B activation. Exogenous addition of leukotriene B₄ (LTB₄) restored NF-B activation reduced by 5-lipoxygenase inhibitors or an LTB₄ receptor antagonist, thus identifying LTB₄ as a mediator in signaling to NF-B. TNF-- and IL-1-induced AA release from cellular membranes was accompanied by phosphorylation of cytosolic PLA₂. Inhibitors of secretory PLA₂ and of 5-lipoxygenase/LTB₄ functionality markedly reduced AA release and nearly completely abolished cytosolic PLA₂ phosphorylation. This demonstrates that secretory PLA₂, through 5-lipoxygenase metabolites, is an essential upstream regulator of cytosolic PLA₂ and AA release. Our results therefore suggest the existence of a functional link between secretory and cytosolic PLA₂ in cytokine-activated keratinocytes, providing a molecular explanation for the participation of both secretory and cytosolic PLA₂ in arachidonic acid signaling and NF-B activation in response to proinflammatory cytokines.

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