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

Cell. 2000 Dec 22;103(7):1071-83. doi: 10.1016/s0092-8674(00)00210-5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3' Untranslated Regions / physiology
  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / immunology
  • Animals
  • Bone Marrow Cells / immunology
  • Cytoplasm / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Female
  • Galactosamine / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology*
  • Lipopolysaccharides / pharmacology*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / immunology*
  • Macrophages, Peritoneal / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 7
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Processing, Post-Transcriptional / drug effects
  • RNA Processing, Post-Transcriptional / immunology*
  • RNA, Messenger / metabolism
  • Shock, Septic / chemically induced
  • Shock, Septic / physiopathology
  • Spleen / cytology
  • Spleen / immunology
  • Thioglycolates / pharmacology
  • Tumor Necrosis Factor-alpha / genetics*

Substances

  • 3' Untranslated Regions
  • Lipopolysaccharides
  • NF-kappa B
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Thioglycolates
  • Tumor Necrosis Factor-alpha
  • Galactosamine
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 7
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse