Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells

Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3274-9. doi: 10.1073/pnas.0511113103. Epub 2006 Feb 16.

Abstract

Engaging mammalian Toll-like receptors (TLRs) activate both the NF-kappaB and mitogen-activated protein kinase signaling pathways. Here we establish that mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands. Despite rescuing TLR-dependent ERK activation in nfkb1(-/-) bone marrow-derived macrophages by using an estrogen receptor-regulated version of the mitogen-activated protein 3 kinase, c-Raf (Raf:ER), CpG or LPS induction of IL-10 was only partially restored in nfkb1(-/-) cells expressing Raf:ER, a finding consistent with NF-kappaB1 regulating IL-10 by a combination of ERK-independent and -dependent mechanisms. Collectively, our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • Cyclopropanes / pharmacology
  • Enzyme Activation / drug effects
  • Gene Expression Regulation
  • Guanosine / analogs & derivatives
  • Guanosine / pharmacology
  • Interleukin-10 / biosynthesis
  • Ligands
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase Kinases / deficiency
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B p50 Subunit / deficiency
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Toll-Like Receptors / metabolism*
  • raf Kinases / metabolism

Substances

  • Cyclopropanes
  • Ligands
  • Lipopolysaccharides
  • N2-cyclopropylamine-guanosine
  • NF-kappa B p50 Subunit
  • Proto-Oncogene Proteins
  • Toll-Like Receptors
  • Guanosine
  • Interleukin-10
  • Nfkb1 protein, mouse
  • raf Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse