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PMID: 15280422 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

RIP links TLR4 to Akt and is essential for cell survival in response to LPS stimulation.

The Journal of experimental medicine ·Vol. 200 ·No. 3 ·2004-08-02 ·Pages 399-404

Vivarelli MS, McDonald D, Miller M, Cusson N, Kelliher M, Geha RS

Abstract

Receptor-interacting protein (RIP) has been reported to associate with tumor necrosis-associated factor (TRAF)2 and TRAF6. Since TRAF2 and TRAF6 play important roles in CD40 signaling and TRAF6 plays an important role in TLR4 signaling, we examined the role of RIP in signaling via CD40 and TLR4. Splenocytes from RIP(-/-) mice proliferated and underwent isotype switching normally in response to anti-CD40-IL-4 but completely failed to do so in response to LPS-IL-4. However, they normally up-regulated TNF-alpha and IL-6 gene expression and CD54 and CD86 surface expression after LPS stimulation. RIP(-/-) splenocytes exhibited increased apoptosis and impaired Akt phosphorylation after LPS stimulation. These results suggest that RIP is essential for cell survival after TLR4 signaling and links TLR4 to the phosphatidylinositol 3 kinase-Akt pathway.

MeSH Terms
Animals Antigens, CD/analysis,physiology B7-2 Antigen Cell Survival Immunoglobulin Class Switching Intercellular Adhesion Molecule-1/analysis Interleukin-6/biosynthesis Lipopolysaccharides/pharmacology Lymphocyte Activation Membrane Glycoproteins/analysis,physiology Mice Mice, Inbred C57BL Phosphatidylinositol 3-Kinases/physiology Phosphorylation Protein Serine-Threonine Kinases/physiology Proteins/physiology Proto-Oncogene Proteins/physiology Proto-Oncogene Proteins c-akt Receptor-Interacting Protein Serine-Threonine Kinases Receptors, Cell Surface/physiology Receptors, Tumor Necrosis Factor/physiology Receptors, Tumor Necrosis Factor, Type I Toll-Like Receptor 4 Toll-Like Receptors Tumor Necrosis Factor-alpha/biosynthesis
Chemicals
Antigens, CD B7-2 Antigen Cd86 protein, mouse Interleukin-6 Lipopolysaccharides Membrane Glycoproteins Proteins Proto-Oncogene Proteins Receptors, Cell Surface Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Toll-Like Receptor 4 Toll-Like Receptors Tumor Necrosis Factor-alpha Intercellular Adhesion Molecule-1 Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Receptor-Interacting Protein Serine-Threonine Kinases Ripk1 protein, mouse
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Vivarelli Marina S
Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
McDonald Douglas
Miller Mendy
Cusson Nicole
Kelliher Michelle
Geha Raif S
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20040446
Published
2004-08-02
Epub
2004-00-26
Pages
399-404
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2211984
Subset
IM
Grants
NIAID NIH HHS · R01 AI031136 · United States
NIGMS NIH HHS · R01 GM061298 · United States
NIAID NIH HHS · AI31136 · United States
External Links
PubMed source DOI: 10.1084/jem.20040446 PMC Full Text View journal details
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