TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway

Calin D. Dumitru, Jeffrey D. Ceci, Christos Tsatsanis, Dimitris Kontoyiannis, Konstantinos Stamatakis, Jun Hsiang Lin, Christos Patriotis, Nancy A. Jenkins, Neal G. Copeland, George Kollias, Philip N. Tsichlis

Research output: Contribution to journalArticle

654 Scopus citations

Abstract

Tpl2 knockout mice produce low levels of TNF-α 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-κB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-α 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-α mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-α. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport, of TNF-α mRNA from the nucleus to the cytoplasm.

Original languageEnglish (US)
Pages (from-to)1071-1083
Number of pages13
JournalCell
Volume103
Issue number7
DOIs
StatePublished - Dec 22 2000

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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