Autoregulation of Th1-mediated inflammation by twist1.
The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor kappaB (NF-kappaB)-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-kappaB, 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-gamma, IL-2, and tumor necrosis factor-alpha, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.
Niesner
Uwe
U
German Rheumatism Research Center Berlin, 10117 Berlin, Germany.
Albrecht
Inka
I
Janke
Marko
M
Doebis
Cornelia
C
Loddenkemper
Christoph
C
Lexberg
Maria H
MH
Eulenburg
Katharina
K
Kreher
Stephan
S
Koeck
Juliana
J
Baumgrass
Ria
R
Bonhagen
Kerstin
K
Kamradt
Thomas
T
Enghard
Philipp
P
Humrich
Jens Y
JY
Rutz
Sascha
S
Schulze-Topphoff
Ulf
U
Aktas
Orhan
O
Bartfeld
Sina
S
Radbruch
Helena
H
Hegazy
Ahmed N
AN
Löhning
Max
M
Baumgart
Daniel C
DC
Duchmann
Rainer
R
Rudwaleit
Martin
M
Häupl
Thomas
T
Gitelman
Inna
I
Krenn
Veit
V
Gruen
Joachim
J
Sieper
Jochen
J
Zeitz
Martin
M
Wiedenmann
Bertram
B
Zipp
Frauke
F
Hamann
Alf
A
Janitz
Michal
M
Scheffold
Alexander
A
Burmester
Gerd R
GR
Chang
Hyun D
HD
Radbruch
Andreas
A
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D007156:Immunologic Memory; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D018664:Interleukin-12