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

doi: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

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 journal › Article › peer-review

6 Scopus citations

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 language	English (US)
Pages (from-to)	1118-1130
Number of pages	13
Journal	Kidney International
Volume	93
Issue number	5
DOIs	https://doi.org/10.1016/j.kint.2017.11.017
State	Published - May 2018
Externally published	Yes

Keywords

T helper 1 cells
Tbet
Treg cells
inflammatory microenvironment
nucleus-transducible form
systemic lupus erythematosus

ASJC Scopus subject areas

Nephrology

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10.1016/j.kint.2017.11.017

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Moon, J. S., Mun, C. H., Kim, J. H., Cho, J. Y., Park, S. D., Park, T. Y., Shin, J. S., Ho, C. C., Park, Y. B., Ghosh, S., Bothwell, A. L. M., Lee, S. W., & Lee, S. K. (2018). Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice. Kidney International, 93(5), 1118-1130. https://doi.org/10.1016/j.kint.2017.11.017

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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.",

keywords = "T helper 1 cells, Tbet, Treg cells, inflammatory microenvironment, nucleus-transducible form, systemic lupus erythematosus",

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}",

note = "Publisher Copyright: {\textcopyright} 2017 International Society of Nephrology",

year = "2018",

month = may,

doi = "10.1016/j.kint.2017.11.017",

language = "English (US)",

volume = "93",

pages = "1118--1130",

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TY - JOUR

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.

KW - T helper 1 cells

KW - Tbet

KW - Treg cells

KW - inflammatory microenvironment

KW - nucleus-transducible form

KW - systemic lupus erythematosus

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U2 - 10.1016/j.kint.2017.11.017

DO - 10.1016/j.kint.2017.11.017

M3 - Article

C2 - 29409726

AN - SCOPUS:85041577944

SN - 0085-2538

VL - 93

SP - 1118

EP - 1130

JO - Kidney International

JF - Kidney International

IS - 5

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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