A20 ZINC-FINGER PROTEIN INHIBITS TNF AND IL-1 SIGNALING

A20 zinc finger protein is a product of a cytokine-induced primary res ponse gene, In this report, we demonstrate that A20 specifically inhib its signal transduction pathways induced by TNF and IL-1, suggesting t hat it functions as a negative regulator of the cytokine response, Ove rexpression of A20 in MCF7 breast carcinoma cells or in WEHI-S fibrosa rcoma tells inhibits apoptosis induced by TNF, whereas cytotoxicity in duced by anti-Fas (anti-CD95), lymphokine-activated killer (LAK) cells , serum starvation, oxidative stress, or okadaic acid is not inhibited , Overexpression of A20 also inhibits TNF-induced activation of phosph olipase A(2) in a similar dose-dependent manner as it inhibits TNF-med iated apoptosis, whereas it does not affect the activation of phosphol ipase A(2) by anti-Fas, Interestingly, A20 also blocks TNF-induced sig nal transduction pathways not directly related to the cytotoxicity, na mely activation of NF-kappa B and AP-1 transcription factors, Activati on of these transcription factors by a functionally related cytokine, IL-1, is also inhibited by A20, whereas activation induced by hydrogen peroxide or phorbol ester is unaffected. Overexpression of A20 does n ot affect the binding of TNF to its cell surface receptors, These data suggest that A20 functions as a negative regulator of TNF and IL-1, i nterfering with signal transduction pathways at an early point followi ng receptor binding but before the activation of various second messen gers, leading to the wide variety of effects induced by these cytokine s.