Epstein‐Barr virus‐induced gene 3 negatively regulates IL‐17, IL‐22 and RORγt

Yang, Jianfei; Yang, Min; Htut, Tin M.; Ouyang, Xinshou; Hanidu, Adedayo; Li, Xiang; Sellati, Rosemarie; Jiang, Huiping; Zhang, Shu; Li, Hongxing; Zhao, Jie; Ting, Adrian T.; Mayer, Lloyd; Unkeless, Jay C.; Labadia, Mark E.; Hodge, Martin R.; Li, Jun; Xiong, Huabao

doi:10.1002/eji.200838145

Cited by 96 publications

(82 citation statements)

References 35 publications

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“…cDNA synthesis and TaqMan Real Time PCR were performed as described previously (25)(26)(27). TaqMan quantitative PCR was performed on a 7900HT Real Time PCR System (Applied Biosystems).…”

Section: Rna Extraction Quantitative Rt-pcrmentioning

confidence: 99%

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Skepner¹,

Ramesh²,

Trocha³

et al. 2014

The Journal of Immunology

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IL-17–producing CD4+Th17 cells, CD8+Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8+ Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23–induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.

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“…cDNA synthesis and TaqMan Real Time PCR were performed as described previously (25)(26)(27). TaqMan quantitative PCR was performed on a 7900HT Real Time PCR System (Applied Biosystems).…”

Section: Rna Extraction Quantitative Rt-pcrmentioning

confidence: 99%

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Skepner¹,

Ramesh²,

Trocha³

et al. 2014

The Journal of Immunology

Self Cite

130

123

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“…or d30 p.i. A combination of IL-17D with EBI3 results in formation of either IL-27, which is associated with negative regulation of Th17 differentiation [38], or of IL-35, an inhibitory cytokine associated with suppressive functions of regulatory T cells [39]. We detected elevated transcription of genes encoding IL-15, associated with IL-2 responsiveness and survival of NK cells [40] and expression of Foxp3 in CD4 1 T cells [41], and IL-16, linked to recruitment of CD4 1 T cells, in particular regulatory T cells [42] in H37Ra-infected iNOS -/-mice at later time points during infection.…”

Section: Adaptive Immune Responsementioning

confidence: 99%

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Beisiegel¹,

Mollenkopf²,

Hahnke³

et al. 2009

Eur J Immunol

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Progression and outcome of tuberculosis is governed by extensive crosstalk between pathogen and host. Analyses of global changes in gene expression during immune response to infection with Mycobacterium tuberculosis (M.tb) can help identify molecular markers of disease state and progression. Global distribution of M.tb strains with different degrees of virulence and drug resistance, especially for the immunocompromised host, make closer analyses of host responses more pressing than ever. Here, we describe global transcriptional responses of inducible nitric oxide synthase-deficient (iNOS -/-) and WT mice infected with two related M.tb strains of markedly different virulence, namely the M.tb laboratory strains H37Rv and H37Ra. Both hosts exhibited highly similar resistance to infection with H37Ra. In contrast, iNOS -/-mice rapidly succumbed to H37Rv, whereas WT mice developed chronic course of disease. By differential analyses, virulence-specific changes in global host gene expression were analyzed to identify molecular markers characteristic for chronic versus acute infection. We identified several markers unique for different stages of disease progression and not previously associated with virulencespecific host responses in tuberculosis.

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“…Moreover, Th17 cells are characterized by the secretion of IL-17 and IL-22, in which IL-17 was regarded to be involved in host defense and protective immunity 62 ; IL-22 was considered to mediate IL-23-induced Th17 cell generation 63 ; and RORγt was found to be the key transcription factor for the differentiation of Th17 cells 64 . Meanwhile, the deletion of EBI3 could also upregulate the expression of IL-17, IL-22 and RORγt, thus confirming the immuno-suppressive effect of IL-35 on the differentiation of Th17 cells as well 65 . However, the precise mechanism hidden behind this phenomenon requires further verification.…”

Section: Il-35 Suppressed the Differentiation Of Th17 Cellsmentioning

confidence: 64%