Autoregulation of Th1-mediated inflammation by twist1

Author:

Niesner Uwe1,Albrecht Inka1,Janke Marko1,Doebis Cornelia2,Loddenkemper Christoph3,Lexberg Maria H.1,Eulenburg Katharina2,Kreher Stephan1,Koeck Juliana1,Baumgrass Ria1,Bonhagen Kerstin4,Kamradt Thomas4,Enghard Philipp1,Humrich Jens Y.1,Rutz Sascha1,Schulze-Topphoff Ulf5,Aktas Orhan5,Bartfeld Sina1,Radbruch Helena5,Hegazy Ahmed N.1,Löhning Max2,Baumgart Daniel C.6,Duchmann Rainer7,Rudwaleit Martin7,Häupl Thomas2,Gitelman Inna8,Krenn Veit9,Gruen Joachim1,Sieper Jochen2,Zeitz Martin7,Wiedenmann Bertram6,Zipp Frauke5,Hamann Alf2,Janitz Michal10,Scheffold Alexander1,Burmester Gerd R.2,Chang Hyun D.1,Radbruch Andreas1

Affiliation:

1. German Rheumatism Research Center Berlin, 10117 Berlin, Germany

2. Department of Rheumatology and Clinical Immunology,

3. Department of Pathology/RCIS,

4. Institute of Immunology, Friedrich Schiller University Jena, Medical School, 07740 Jena, Germany

5. Cecilie Vogt Clinic for Neurology in the HKBB, Charité–University Medicine Berlin, and Max Delbrück Center for Molecular Medicine, 10117 Berlin, Germany

6. Department of Medicine, Division of Hepatology and Gastroenterology, Charité-University Medicine Berlin, Humboldt University of Berlin, 13344 Berlin, Germany

7. Medical Clinic I (Gastroenterology, Rheumatology, Infectiology), Charité-University Medicine Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany

8. Department of Virology and Developmental Genetics, Ben Gurion University of the Negev, Beer Sheva 84105, Israel

9. Institute of Pathology, Charité-University Medicine Berlin, 10117 Berlin, Germany

10. Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, 14195 Berlin, Germany

Abstract

The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor κB (NF-κB)–dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-κB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-γ, IL-2, and tumor necrosis factor-α, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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