Transcription of Il17 and Il17f Is Controlled by Conserved Noncoding Sequence 2

Wang, Xiaohu; Zhang, Yibing; Yang, Xuexian O.; Nurieva, Roza; Chang, Seon Hee; Ojeda, Sandra S.; Kang, Hong Soon; Schluns, Kimberly S.; Gui, Jian‐Fang; Jetten, Anton M.; Dong, Chen

doi:10.1016/j.immuni.2011.10.019

Cited by 112 publications

(107 citation statements)

References 38 publications

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“…CBP/p300 is thought to be involved at an early stage, consistent with our data showing key sensitivity of human IL 17A transcription to CBP/p300 inhibition (38,39). In murine Th17 cells, conserved noncoding sequence 2 (CNS2) is important to drive Il 17 gene transcription in coordination with RORγt and is bound by p300 (24). However, expression of Il 17f is only partially dependent on CNS2, a possible explanation for the CBP30 specificity.…”

Section: Discussionsupporting

confidence: 88%

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CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Hammitzsch

Tallant

Fedorov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

221

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Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.CBP/p300 | bromodomain | epigenetic inhibitors | Th17 | ankylosing spondylitis

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Section: Discussionsupporting

confidence: 88%

“…Cytokinedriven induction of the transcriptional Th17 profile is strongly mediated by epigenetic mechanisms (23), one facilitator being the transcriptional coactivator p300. Recent studies demonstrated that p300 binds to the Il 17a promoter in murine Th17 cells and facilitates chromatin accessibility (24).…”

mentioning

confidence: 99%

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Hammitzsch

Tallant

Fedorov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

221

200

View full text Add to dashboard Cite

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“…5C). This region encompasses the conserved noncoding sequence (CNS)-2 enhancer (16). We then generated reporter constructs with a minimal proximal promoter (−301/+37) linked to different portions of this critical region.…”

Section: Irf3 Interacts With Rorγt and Limits Its Recruitment To The mentioning

confidence: 99%

Interferon regulatory factor 3 controls interleukin-17 expression in CD8 T lymphocytes

Lendonck

Tonon

Nguyen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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IFN regulatory factor (IRF) 3 plays a key role in innate responses against viruses. Herein we assessed its contribution to T-cell activation. We observed that poly(I:C)-induced IRF3 activation in CD8 T cells represses IL-17 expression in a type I IFN-independent fashion. Even in the absence of poly(I:C), polyclonally activated naïve IRF3−/− CD8 T cells expressed high levels of IL-17 and IL-23Rin comparison with wild-type cells. Furthermore, IRF3 −/− OT1 cells adoptively transferred into wild-type hosts also produced higher IL-17 levels upon immunization than their wild-type counterparts. This phenotype could be reversed by ectopic expression of IRF3, confirming that this effect is intrinsic to T cells. We show that IRF3 directly interacts with RORγt in the cytoplasm through its IRF interaction domain and limits its ability to bind and transactivate the IL-17 promoter. These observations uncover an unexpected role of IRF3 in the control of CD8 T-cell polarization.transcription factor | cytokine | Th17 | Tc17 | enhancer

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“…Interestingly, multiple RORγ-binding sites were identified in the IL-17/IL-17F gene locus. To test the function of these elements in the transcriptional regulation, Wang et al [5] deleted one cis element, CNS2 in the IL-17/IL-17F gene locus and found that RORγ-dependent IL-17 transcription was almost completely suppressed. Moreover, epigenetic activation of the gene locus was affected, though how RORγ interacts with the epigenetic machineries remains unknown at this stage.…”

mentioning

confidence: 99%