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

• Published in: Nature (London) Vol. 416; no. 6877; pp. 190 - 194
• Main Authors: Cheng, Genhong, Chin, Arnold I, Dempsey, Paul W, Bruhn, Kevin, Miller, Jeff F, Xu, Yang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 14.03.2002; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Bacteria; Biological and medical sciences; CARDIAK protein; Carrier Proteins - metabolism; Cell Line; Drosophila Proteins; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Deletion; General aspects. Ontogeny. Phylogeny; Humans; Immunity, Innate - immunology; Immunobiology; Immunoglobulin Class Switching; Immunology; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-12 - immunology; Interleukin-18 - immunology; Killer Cells, Natural - immunology; Lipopolysaccharides - immunology; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeria monocytogenes - physiology; Listeriosis - immunology; Listeriosis - metabolism; Listeriosis - pathology; Lymphocyte Activation; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Membrane Glycoproteins - metabolism; Mice; Mice, Knockout; Microorganisms; Molecular Sequence Data; NF-kappa B - metabolism; Nod1 protein; Nod1 Signaling Adaptor Protein; Pathogens; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - immunology; Protein-Serine-Threonine Kinases - metabolism; Proteins; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Cell Surface - metabolism; RICK protein; Rip2 protein; Rodents; Shock, Septic - chemically induced; Shock, Septic - immunology; STAT4 protein; Th1 Cells - cytology; Th1 Cells - immunology; Th1 Cells - metabolism; TLR4 protein; Toll-Like Receptor 4; Toll-Like Receptors; Active immunity; Natural immunity; Immune response
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/416190a

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-κB, whereas dominant negative Rip2 inhibited NF-κB 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-γ 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.