Nature Immunology - 7, 946 - 953 (2006)
Published online: 13 August 2006
Interleukin 18–independent engagement of interleukin 18 receptor- is required for autoimmune inflammation
Ilona Gutcher1, Eduard Urich1, Karina Wolter2, Marco Prinz2 & Burkhard Becher1
1 Neuroimmunology Unit, Neurology Clinic, University of Zurich, 8057 Zurich, Switzerland
2 Institute of Neuropathology, Georg-August-University, D-37075 Gottingen, Germany.
Correspondence should be addressed to Burkhard Becher burkhard.becher@neuroimm.unizh.ch
T helper type 1 (TH1) lymphocytes are considered to be the main pathogenic cell type responsible for organ-specific autoimmune inflammation. As interleukin 18 (IL-18) is a cofactor with IL-12 in promoting TH1 cell development, we examined the function of IL-18 and its receptor, IL-18R, in autoimmune central nervous system inflammation. Similar to IL-12-deficient mice, IL-18-deficient mice were susceptible to experimental autoimmune encephalomyelitis. In contrast, IL-18R-deficient mice were resistant to experimental autoimmune encephalomyelitis, indicating involvement of an IL-18R ligand other than IL-18 with encephalitogenic properties. Moreover, engagement of IL-18R on antigen-presenting cells was required for the generation of pathogenic IL-17-producing T helper cells. Thus, IL-18 and TH1 cells are dispensable, whereas IL-18R and IL-17-producing T helper cells are required, for autoimmune central nervous system inflammation.
Nature Immunology - 7, 929 - 936 (2006)
Published online: 13 August 2006
Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells
Marcel Batten1, 4, Ji Li1, 4, Sothy Yi1, Noelyn M Kljavin1, Dimitry M Danilenko2, Sophie Lucas3, James Lee1, Frederic J de Sauvage1 & Nico Ghilardi1
1 Department of Molecular Biology, South San Francisco, California 94080, USA.
2 Department of Pathology, Genentech, South San Francisco, California 94080, USA.
3 Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Belgium.
4 These authors contributed equally to this work.
Correspondence should be addressed to Nico Ghilardi ghilardi@gene.com
Interleukin 27 (IL-27) was first characterized as a proinflammatory cytokine with T helper type 1–inducing activity. However, subsequent work has demonstrated that mice deficient in IL-27 receptor (IL-27R) show exacerbated inflammatory responses to a variety of challenges, suggesting that IL-27 has important immunoregulatory functions in vivo. Here we demonstrate that IL-27R-deficient mice were hypersusceptible to experimental autoimmune encephalomyelitis and generated more IL-17-producing T helper cells. IL-27 acted directly on effector T cells to suppress the development of IL-17-producing T helper cells mediated by IL-6 and transforming growth factor-. This suppressive activity was dependent on the transcription factor STAT1 and was independent of interferon-. Finally, IL-27 suppressed IL-6-mediated T cell proliferation. These data provide a mechanistic explanation for the IL-27-mediated immune suppression noted in several in vivo models of inflammation.
Nature Immunology - 7, 937 - 945 (2006)
Published online: 13 August 2006
Interleukin 27 negatively regulates the development of interleukin 17–producing T helper cells during chronic inflammation of the central nervous system
Jason S Stumhofer1, Arian Laurence2, Emma H Wilson1, Elaine Huang1, Cristina M Tato2, Leanne M Johnson1, Alejandro V Villarino1, Qiulong Huang3, Akihiko Yoshimura4, David Sehy3, Christiaan J M Saris5, John J O'Shea2, Lothar Hennighausen6, Matthias Ernst7 & Christopher A Hunter1
1 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6008, USA.
2 Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Muskoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
3 New Technologies Department, eBioscience, San Diego, California 92121, USA.
4 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582 Japan.
5 Department of Inflammation Research, Amgen, Thousand Oaks, California 91320, USA.
6 Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
7 Ludwig Institute for Cancer Research, Parkville, Victoria 3050, Australia.
Correspondence should be addressed to Christopher A Hunter chunter@vet.upenn.edu
Studies have focused on the events that influence the development of interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize TH-17 cell effector responses. Here we show that IL-27 receptor–deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development TH-17 cells induced by IL-6 and transforming growth factor-, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of TH-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.
Nature Immunology - 7, 954 - 961 (2006)
Published online: 6 August 2006
Inhibition of transcription factor NF-B in the central nervous system ameliorates autoimmune encephalomyelitis in mice
Geert van Loo1, Rossana De Lorenzi1, Hauke Schmidt2, Marion Huth1, Alexander Mildner2, Marc Schmidt-Supprian3, Hans Lassmann4, Marco R Prinz2, 6 & Manolis Pasparakis1, 5, 6
1 European Molecular Biology Laboratory Mouse Biology Unit, I-00016 Monterotondo, Italy.
2 Department of Neuropathology, Georg August University, D-37075 Göttingen, Germany.
3 The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
4 Brain Research Institute, University of Vienna, A-1090 Vienna, Austria.
5 Institute for Genetics, University of Cologne, D-50674 Cologne, Germany.
6 These authors contributed equally to this work.
Correspondence should be addressed to Manolis Pasparakis pasparakis@uni-koeln.de
Activation of transcription factor NF-B in the central nervous system (CNS) has been linked to autoimmune demyelinating disease; however, it remains unclear whether its function is protective or pathogenic. Here we show that CNS-restricted ablation of 'upstream' NF-B activators NEMO or IKK2 but not IKK1 ameliorated disease pathology in a mouse model of multiple sclerosis, suggesting that 'canonical' NF-B activation in cells of the CNS has a mainly pathogenic function in autoimmune demyelinating disease. NF-B inhibition prevented the expression of proinflammatory cytokines, chemokines and the adhesion molecule VCAM-1 from CNS-resident cells. Thus, NF-B-dependent gene expression in non–microglial cells of the CNS provides a permissive proinflammatory milieu that is critical for CNS inflammation and tissue damage in autoimmune demyelinating disease. |
