TGF-beta suppresses IFN-gamma induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression.

Lee, Yi Ju; Han, Yi; Lu, Hong; Nguyen, Vincent; Qin, Hongwei; Howe, Philip H.; Hocevar, Barbara A.; Boss, Jeremy M.; Ransohoff, Richard M.; Benveniste, Etty N.

doi:10.4049/jimmunol.158.5.2065

Cited by 153 publications

(13 citation statements)

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“…2A). IFN-␥-induced CIITA mRNA accumulation preceded that of DRA mRNA expression by ϳ3 h, as observed in other cell types (13). TNF-␣ inhibited both IFN-␥-induced CIITA and MHC class II DR mRNA by ϳ68% and ϳ85%, respectively (Fig.…”

Section: Tnf-␣ Inhibits Ifn-␥ Induction Of Ciita and Mhc Class II Mrn...supporting

confidence: 72%

“…Previously, we showed that either TGF-␤ or IFN-␤ efficiently suppressed MHC class II transcription induced by IFN-␥ in HT1080 or its derivatives (13,18). TNF-␣-mediated induction or activation of these cytokines has been reported.…”

Section: Tnf-␣ Inhibits Ifn-␥ Induction Of Ciita and Mhc Class II Mrn...mentioning

confidence: 94%

“…IFN-␥ can modulate or induce MHC class II expression in MHC class II-positive and -negative cells (1,5). Induction of MHC class II genes by IFN-␥ involves an indirect mechanism, requiring synthesis of a factor termed class II trans-activator (CIITA) 3 that couples IFN-␥ stimulation and MHC class II expression (11)(12)(13). MHC class II ex-pression is quantitatively controlled by the level of CIITA, which itself is tightly regulated by IFN-␥ (11,14).…”

Section: Tnf-␣ Suppresses Ifn-␥-induced Mhc Class II Expression In Ht...mentioning

confidence: 99%

“…g/ml G418. HT1080.CIITA.tet cells, described previously (13), were maintained in same medium with 1 g/ml tet. Recombinant human IFN-␥ and TNF-␣ were obtained from Genentech (South San Francisco, CA) and Becton Dickinson Labware (Bedford, MA), respectively.…”

Section: Tnf-␣ Suppresses Ifn-␥-induced Mhc Class II Expression In Ht...mentioning

confidence: 99%

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TNF-α Suppresses IFN-γ-Induced MHC Class II Expression in HT1080 Cells by Destabilizing Class IItrans-Activator mRNA

Han¹,

Zhou²,

Ransohoff

1999

The Journal of Immunology

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Precise regulation of MHC class II gene expression is crucial for development and function of the immune system. Class II trans-activator (CIITA) has been shown to be required for constitutive and IFN-γ-induced MHC class II transcription. TNF-α is commonly coexpressed with IFN-γ during immune-mediated inflammatory responses and modulates IFN-γ-stimulated MHC class II expression. The effect of TNF-α on MHC class II expression depends on cell type and cellular differentiation state. We show here that TNF-α suppresses IFN-γ-induced CIITA mRNA accumulation, resulting in decreased MHC class II expression in human fibrosarcoma HT1080 cells. TNF-α also inhibits CIITA mRNA accumulation and protein expression in a tetracycline-regulated system without affecting promoter activity. CIITA mRNA, regulated by either IFN-γ or tetracycline, was destabilized in the presence of TNF-α, suggesting that TNF-α utilizes a distinct mechanism to suppress MHC class II expression in HT1080 cells. Consistent with this interpretation, TNF-α blocked IFN-γ-induced CIITA and MHC class II expression in mutant cells that are unresponsive to TGF-β or IFN-β. This is the first instance in which MHC class II expression is inhibited by destabilizing CIITA mRNA.

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Section: Tnf-␣ Inhibits Ifn-␥ Induction Of Ciita and Mhc Class II Mrn...supporting

confidence: 72%

Section: Tnf-␣ Inhibits Ifn-␥ Induction Of Ciita and Mhc Class II Mrn...mentioning

confidence: 94%

Section: Tnf-␣ Suppresses Ifn-␥-induced Mhc Class II Expression In Ht...mentioning

confidence: 99%

Section: Tnf-␣ Suppresses Ifn-␥-induced Mhc Class II Expression In Ht...mentioning

confidence: 99%

See 2 more Smart Citations

TNF-α Suppresses IFN-γ-Induced MHC Class II Expression in HT1080 Cells by Destabilizing Class IItrans-Activator mRNA

Han¹,

Zhou²,

Ransohoff

1999

The Journal of Immunology

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“…TGF-β1 and TGF-β2 have been reported to downregulate constitutive and IFN-g-induced MHC class I and MHC class II surface expression (Donnet-Hughes et al, 1995; Ma and Niederkorn, 1995; Berglund et al, 2017). The mechanism by which TGF-β regulates MHC I expression has not yet been established, but TGF-β1 and TGF-β2 downregulate MHC class II gene expression by inhibiting its master transcription factor, the class II transactivator (CIITA), through a Smad3-dependent mechanism (Lee et al, 1997; Dong et al, 2001; Romieu-Mourez et al, 2007). Based on in vivo knockout studies, regulation of MHC molecules by TGF-β appears to play an important role in modulating adaptive immune responses.…”

Section: Introductionmentioning

confidence: 99%

TGF-β downregulates antigen processing and presentation genes and MHC I surface expression through a Smad3-dependent mechanism

Berglund¹,

Hinson²,

Schnabel³

2023

Preprint

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Regulation of MHC I surface expression by TGF-β is important for controlling cell-mediated immune responses, but how TGF-β downregulates MHC I is unknown. We investigated this mechanism using flow cytometry and RNA-sequencing to identify the major TGF-β signaling pathway and target genes involved. All three isoforms of TGF-β were found to have similar abilities to downregulate constitutive MHC I surface expression. Inhibiting the type I TGF-β receptor, ALK5, as well the canonical TGF-β signaling molecule Smad3, prevented TGF-β from downregulating MHC I surface expression. RNA-sequencing from horse and human mesenchymal stem cells revealed that multiple genes associated with antigen processing and presentation were downregulated in TGF-β-treated cells with B2M and ERAP1 being downregulated in both species. While downregulation of MHC I surface expression a slow process that continued past 24 hours after TGF-β treatment, downregulation of gene expression of ERAP1 occurred within 12 hours after treatment. B2M expression was not consistently downregulated until after 24 hours and TAP2 expression was inconsistent over a 72-hour period, although it was significantly downregulated at 12 hours after TGF-β treatment. This data supports that TGF-β downregulates antigen processing and presentation genes resulting in decreased surface expression of MHC I through a Smad3-dependent mechanism.

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Modulation of cellular tryptophan metabolism in human fibroblasts by transforming growth factor-β: Selective inhibition of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA synthetase gene expression

et al. 1998

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Alterations in the rate of cellular tryptophan metabolism are involved in mediating important biological activities associated with cytokines and growth factors. Indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase are enzymes of tryptophan metabolism whose expression in a variety of cells and tissues is highly inducible by interferon-gamma (IFN-gamma). Transforming growth factor-beta (TGF-beta) antagonizes many cellular responses to IFN-gamma. The interaction of these two cytokines plays an important role in maintaining homeostasis during inflammation and repair. In human skin and synovial fibroblasts in vitro, TGF-beta caused time- and dose-dependent abrogation of IFN-gamma-stimulated expression of IDO and tryptophanyl-tRNA synthetase mRNAs. The inhibition was selective and did not appear to be due to down-regulation of IFN-gamma signaling by TGF-beta. In parallel with its effect on IDO mRNA expression, TGF-beta caused a marked reduction in intracellular IDO protein levels and abrogated IDO activity and tryptophan catabolism in these cells induced by IFN-gamma. IFN-gamma caused a rapid and striking increase in the amount of IDO heterogeneous nuclear pre-mRNA and induced transcription of the IDO gene, as demonstrated by transient transfection assays. TGF-beta partially reversed this stimulation. IFN regulatory factor (IRF)-1 and stat1 are cellular intermediates in IFN signaling. Both are implicated in activation of IDO transcription in response to IFN-gamma. The stimulation by IFN-gamma of IRF-1 protein and mRNA expression was not prevented by treatment of fibroblasts with TGF-beta. Furthermore, gel mobility shift assays indicated that TGF-beta did not inhibit the induction of stat1 and IRF-1 binding activity to their cognate DNA recognition sites in the IDO gene promoter. In contrast, the stability of IDO mRNA transcripts was reduced in fibroblasts treated with TGF-beta, as shown by determination of mRNA half-lives following blockade of transcription with 5,6-dichlorobenzimidazole riboside. The findings indicate that TGF-beta prevents the induction of IDO and tryptophanyl-tRNA synthetase gene expression in fibroblasts. The repression of IDO expression by TGF-beta is mediated at both transcriptional and posttranscriptional levels. These results implicate TGF-beta in the negative regulation of tryptophan metabolism, provide evidence for the molecular basis of this regulation, and indicate that cellular tryptophan metabolism is under tight immunological control.

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TGF-beta suppresses IFN-gamma induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression.

Cited by 153 publications

References 0 publications

TNF-α Suppresses IFN-γ-Induced MHC Class II Expression in HT1080 Cells by Destabilizing Class IItrans-Activator mRNA

TNF-α Suppresses IFN-γ-Induced MHC Class II Expression in HT1080 Cells by Destabilizing Class IItrans-Activator mRNA

TGF-β downregulates antigen processing and presentation genes and MHC I surface expression through a Smad3-dependent mechanism

Modulation of cellular tryptophan metabolism in human fibroblasts by transforming growth factor-β: Selective inhibition of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA synthetase gene expression

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