Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arthritis, Experimental / genetics
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Arthritis, Experimental / immunology
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Arthritis, Experimental / metabolism
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Arthritis, Experimental / pathology
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Base Sequence
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Colitis, Ulcerative / genetics
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Colitis, Ulcerative / immunology
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Colitis, Ulcerative / metabolism
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Crohn Disease / genetics
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Crohn Disease / immunology
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Crohn Disease / metabolism
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DNA Primers / genetics
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Gene Expression
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Homeostasis
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Humans
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Immunologic Memory
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Inflammation / etiology*
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Inflammation / genetics
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Inflammation / metabolism
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Inflammation / pathology
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Interleukin-12 / metabolism
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Lymphocyte Activation
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Inbred MRL lpr
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Mice, Knockout
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Mice, SCID
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Mice, Transgenic
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NF-kappa B / metabolism
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NFATC Transcription Factors / metabolism
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Signal Transduction
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Th1 Cells / immunology*
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Th1 Cells / metabolism
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Twist-Related Protein 1 / deficiency
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Twist-Related Protein 1 / genetics
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Twist-Related Protein 1 / metabolism*
Substances
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DNA Primers
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NF-kappa B
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NFATC Transcription Factors
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Nuclear Proteins
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TWIST1 protein, human
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Twist-Related Protein 1
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Twist1 protein, mouse
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Interleukin-12