Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice

Jae Seung Moon, Chin Hee Mun, Jung Ho Kim, Jen Young Cho, Sung Dong Park, Tae Yoon Park, Jin Su Shin, Chun Chang Ho, Yong Beom Park, Sankar Ghosh, Alfred L.M. Bothwell, Sang Won Lee, Sang Kyou Lee

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Excessive expression of Tbet and IFNγ is evidence of systemic lupus erythematosus (SLE) in lupus patients. In this study, the nucleus-transducible form of Transcription Modulation Domain (TMD) of Tbet (ntTbet-TMD), which is a fusion protein between Protein Transduction Domain Hph-1 (Hph-1-PTD) and the TMD of Tbet comprising DNA binding domain and isotype-specific domain, was generated to inhibit Tbet-mediated transcription in the interactomic manner. ntTbet-TMD was effectively delivered into the nucleus of the cells and specifically inhibited Tbet-mediated transcription without influencing the differentiation of other T cell subsets and signaling events for T cell activation. The severity of nephritis was significantly reduced by ntTbet-TMD as effectively as methylprednisolone in lupus-prone mice. The number of Th1, Th2 or Th17 cells and the secretion of their cytokines substantially decreased in the spleen and kidney of lupus-prone mice by ntTbet-TMD treatment. In contrast to methylprednisolone, the marked increase of Treg cells and the secretion of their immunosuppressive cytokine were detected in the spleen of (NZB/NZW) F1 mice treated with ntTbet-TMD. Thus, ntTbet-TMD can improve nephritis in lupus-prone mice by modulating the overall pro-inflammatory micro-environment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases.

Original languageEnglish
Pages (from-to)1118-1130
Number of pages13
JournalKidney International
Volume93
Issue number5
DOIs
Publication statusPublished - 2018 May

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Lupus Nephritis
Methylprednisolone
T-Lymphocyte Subsets
Spleen
Cytokines
Th17 Cells
Th2 Cells
Th1 Cells
Nephritis
Regulatory T-Lymphocytes
Immunosuppressive Agents
Cell Nucleus
Systemic Lupus Erythematosus
Autoimmune Diseases
T-Lymphocytes
Kidney
DNA
Therapeutics
Proteins

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Moon, Jae Seung ; Mun, Chin Hee ; Kim, Jung Ho ; Cho, Jen Young ; Park, Sung Dong ; Park, Tae Yoon ; Shin, Jin Su ; Ho, Chun Chang ; Park, Yong Beom ; Ghosh, Sankar ; Bothwell, Alfred L.M. ; Lee, Sang Won ; Lee, Sang Kyou. / Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice. In: Kidney International. 2018 ; Vol. 93, No. 5. pp. 1118-1130.
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title = "Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice",
abstract = "Excessive expression of Tbet and IFNγ is evidence of systemic lupus erythematosus (SLE) in lupus patients. In this study, the nucleus-transducible form of Transcription Modulation Domain (TMD) of Tbet (ntTbet-TMD), which is a fusion protein between Protein Transduction Domain Hph-1 (Hph-1-PTD) and the TMD of Tbet comprising DNA binding domain and isotype-specific domain, was generated to inhibit Tbet-mediated transcription in the interactomic manner. ntTbet-TMD was effectively delivered into the nucleus of the cells and specifically inhibited Tbet-mediated transcription without influencing the differentiation of other T cell subsets and signaling events for T cell activation. The severity of nephritis was significantly reduced by ntTbet-TMD as effectively as methylprednisolone in lupus-prone mice. The number of Th1, Th2 or Th17 cells and the secretion of their cytokines substantially decreased in the spleen and kidney of lupus-prone mice by ntTbet-TMD treatment. In contrast to methylprednisolone, the marked increase of Treg cells and the secretion of their immunosuppressive cytokine were detected in the spleen of (NZB/NZW) F1 mice treated with ntTbet-TMD. Thus, ntTbet-TMD can improve nephritis in lupus-prone mice by modulating the overall pro-inflammatory micro-environment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases.",
author = "Moon, {Jae Seung} and Mun, {Chin Hee} and Kim, {Jung Ho} and Cho, {Jen Young} and Park, {Sung Dong} and Park, {Tae Yoon} and Shin, {Jin Su} and Ho, {Chun Chang} and Park, {Yong Beom} and Sankar Ghosh and Bothwell, {Alfred L.M.} and Lee, {Sang Won} and Lee, {Sang Kyou}",
year = "2018",
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doi = "10.1016/j.kint.2017.11.017",
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Moon, JS, Mun, CH, Kim, JH, Cho, JY, Park, SD, Park, TY, Shin, JS, Ho, CC, Park, YB, Ghosh, S, Bothwell, ALM, Lee, SW & Lee, SK 2018, 'Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice', Kidney International, vol. 93, no. 5, pp. 1118-1130. https://doi.org/10.1016/j.kint.2017.11.017

Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice. / Moon, Jae Seung; Mun, Chin Hee; Kim, Jung Ho; Cho, Jen Young; Park, Sung Dong; Park, Tae Yoon; Shin, Jin Su; Ho, Chun Chang; Park, Yong Beom; Ghosh, Sankar; Bothwell, Alfred L.M.; Lee, Sang Won; Lee, Sang Kyou.

In: Kidney International, Vol. 93, No. 5, 05.2018, p. 1118-1130.

Research output: Contribution to journalArticle

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T1 - Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice

AU - Moon, Jae Seung

AU - Mun, Chin Hee

AU - Kim, Jung Ho

AU - Cho, Jen Young

AU - Park, Sung Dong

AU - Park, Tae Yoon

AU - Shin, Jin Su

AU - Ho, Chun Chang

AU - Park, Yong Beom

AU - Ghosh, Sankar

AU - Bothwell, Alfred L.M.

AU - Lee, Sang Won

AU - Lee, Sang Kyou

PY - 2018/5

Y1 - 2018/5

N2 - Excessive expression of Tbet and IFNγ is evidence of systemic lupus erythematosus (SLE) in lupus patients. In this study, the nucleus-transducible form of Transcription Modulation Domain (TMD) of Tbet (ntTbet-TMD), which is a fusion protein between Protein Transduction Domain Hph-1 (Hph-1-PTD) and the TMD of Tbet comprising DNA binding domain and isotype-specific domain, was generated to inhibit Tbet-mediated transcription in the interactomic manner. ntTbet-TMD was effectively delivered into the nucleus of the cells and specifically inhibited Tbet-mediated transcription without influencing the differentiation of other T cell subsets and signaling events for T cell activation. The severity of nephritis was significantly reduced by ntTbet-TMD as effectively as methylprednisolone in lupus-prone mice. The number of Th1, Th2 or Th17 cells and the secretion of their cytokines substantially decreased in the spleen and kidney of lupus-prone mice by ntTbet-TMD treatment. In contrast to methylprednisolone, the marked increase of Treg cells and the secretion of their immunosuppressive cytokine were detected in the spleen of (NZB/NZW) F1 mice treated with ntTbet-TMD. Thus, ntTbet-TMD can improve nephritis in lupus-prone mice by modulating the overall pro-inflammatory micro-environment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases.

AB - Excessive expression of Tbet and IFNγ is evidence of systemic lupus erythematosus (SLE) in lupus patients. In this study, the nucleus-transducible form of Transcription Modulation Domain (TMD) of Tbet (ntTbet-TMD), which is a fusion protein between Protein Transduction Domain Hph-1 (Hph-1-PTD) and the TMD of Tbet comprising DNA binding domain and isotype-specific domain, was generated to inhibit Tbet-mediated transcription in the interactomic manner. ntTbet-TMD was effectively delivered into the nucleus of the cells and specifically inhibited Tbet-mediated transcription without influencing the differentiation of other T cell subsets and signaling events for T cell activation. The severity of nephritis was significantly reduced by ntTbet-TMD as effectively as methylprednisolone in lupus-prone mice. The number of Th1, Th2 or Th17 cells and the secretion of their cytokines substantially decreased in the spleen and kidney of lupus-prone mice by ntTbet-TMD treatment. In contrast to methylprednisolone, the marked increase of Treg cells and the secretion of their immunosuppressive cytokine were detected in the spleen of (NZB/NZW) F1 mice treated with ntTbet-TMD. Thus, ntTbet-TMD can improve nephritis in lupus-prone mice by modulating the overall pro-inflammatory micro-environment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases.

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