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Involvement of receptor-interacting protein 2 in innate and adaptive immune responses.

Host defences to microorganisms rely on a coordinated interplay between the innate and adaptive responses of immunity. Infection with intracellular bacteria triggers an immediate innate response requiring macrophages, neutrophils and natural killer cells, whereas subsequent activation of an adaptive response through development of T-helper subtype 1 cells (TH1) proceeds during persistent infection. To understand the physiological role of receptor-interacting protein 2 (Rip2), also known as RICK and CARDIAK, we generated mice with a targeted disruption of the gene coding for Rip2. Here we show that Rip2-deficient mice exhibit a profoundly decreased ability to defend against infection by the intracellular pathogen Listeria monocytogenes. Rip2-deficient macrophages infected with L. monocytogenes or treated with lipopolysaccharide (LPS) have decreased activation of NF-kappaB, whereas dominant negative Rip2 inhibited NF-kappaB activation mediated by Toll-like receptor 4 and Nod1. In vivo, Rip2-deficient mice were resistant to the lethal effects of LPS-induced endotoxic shock. Furthermore, Rip2 deficiency results in impaired interferon-gamma production in both TH1 and natural killer cells, attributed in part to defective interleukin-12-induced Stat4 activation. Our data reflect requirements for Rip2 in multiple pathways regulating immune and inflammatory responses.

Pubmed ID: 11894097

Authors

  • Chin AI
  • Dempsey PW
  • Bruhn K
  • Miller JF
  • Xu Y
  • Cheng G

Journal

Nature

Publication Data

March 14, 2002

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins
  • Cell Line
  • Drosophila Proteins
  • Gene Deletion
  • Humans
  • Immunity, Innate
  • Immunoglobulin Class Switching
  • Interferon-gamma
  • Interleukin-12
  • Interleukin-18
  • Killer Cells, Natural
  • Lipopolysaccharides
  • Listeria monocytogenes
  • Listeriosis
  • Lymphocyte Activation
  • Macrophages
  • Membrane Glycoproteins
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • NF-kappa B
  • Nod1 Signaling Adaptor Protein
  • Protein-Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Receptors, Cell Surface
  • Shock, Septic
  • Th1 Cells
  • Toll-Like Receptor 4
  • Toll-Like Receptors