title: Involvement of receptor-interacting protein 2 in innate and adaptive immune responses.
abstract: 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.
authors.affiliation: Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Arnold I
authors.initials: AI
authors.lastname: Chin
authors.forename: Paul W
authors.initials: PW
authors.lastname: Dempsey
authors.forename: Kevin
authors.initials: K
authors.lastname: Bruhn
authors.forename: Jeff F
authors.initials: JF
authors.lastname: Miller
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D029721:Drosophila Proteins; D017353:Gene Deletion; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology / Q000502:physiology; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D029721:Drosophila Proteins; D020382:Interleukin-18; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse