Phospholipase A(2) inhibitors and leukotriene synthesis inhibitors block TNF-induced NF-kappa B activation

Tumour necrosis factor (TNF) is a key regulator of inflammation and immunit y. The cellular effects exerted by TNF depends, apart from NF-kappa B-direc ted gene transcription, largely on its ability to activate phospholipase A( 2) (PLA(2)), yielding the release of arachidonic acid (AA) and its metaboli tes. AA metabolites, especially the leukotrienes, act as second messengers in TNF receptor signalling, as different inhibitors of AA metabolism impair a variety of TNF-induced biochemical events. The role, however, of AA and its metabolites in TNF-induced NF-kappa B activation is still obscure. Here me report that 4-bromophenacyl bromide (4-BPB; an inhibitor of PLA(2)), no rdihydroguaretic acid (NDGA; a 5-lipoxygenase inhibitor), as well as MK-886 [an inhibitor of 5-lipoxygenase-activating protein (FLAP)] interfere with TNF-induced NF-kappa B-mediated transactivation. However, only 4-BPB inhibi ted the DNA-binding activity of NF-kappa B, whereas NDGA and MK-886 did not . Thus, different inhibitors interfere at different points in TNF-induced s ignalling leading to NF-kappa B-dependent transcription. Artificial inducti on of AA metabolism induced neither DNA-binding activity of NF-kappa B nor NF-kappa B-dependent transactivation, It was concluded that although TNF-in duced signalling to NF-kappa B-dependent transcription is sensitive to inhi bitors of AA metabolism at multiple points during this signalling, AA relea se is essential but not sufficient for NF-kappa B activation. (C) 1999 Acad emic Press.