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Dumitru CD , Ceci JD , Tsatsanis C , Kontoyiannis D , Stamatakis K , Lin JH , Patriotis C , Jenkins NA , Copeland NG , Kollias G , Tsichlis PN
TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway
Cell. 2000 Dec 22;103(7) :1071-83
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Tpl2 knockout mice produce low levels of TNF-alpha when exposed to lipopolysaccharide (LPS) and they are resistant to LPS/D-Galactosamine-induced pathology. LPS stimulation of peritoneal macrophages from these mice did not activate MEK1, ERK1, and ERK2 but did activate JNK, p38 MAPK, and NF-kappaB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-alpha induction by experiments showing that normal murine macrophages treated with the MEK inhibitor PD98059 exhibit a similar defect. Deletion of the AU-rich motif in the TNF-alpha mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-alpha. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport of TNF-alpha mRNA from the nucleus to the cytoplasm.
21097707 0092-8674 Journal Article