Critical role of transmethylation in TLR signaling and systemic lupus erythematosus

Virginie Tardif; Yulia Manenkova; Michael Berger; Kasper Hoebe; Jian Ping Zuo; Chong Yuan; Dwight H. Kono; Argyrios N. Theofilopoulos; Brian R. Lawson

doi:10.1016/j.clim.2013.02.018

Critical role of transmethylation in TLR signaling and systemic lupus erythematosus

Virginie Tardif, Yulia Manenkova, Michael Berger, Kasper Hoebe, Jian Ping Zuo, Chong Yuan, Dwight H. Kono, Argyrios N. Theofilopoulos, Brian R. Lawson

Research output: Contribution to journal › Article › peer-review

Abstract

Post-translational protein modifications can play a significant role in immune cell signaling. Recently, we showed that inhibition of transmethylation curtails experimental autoimmune encephalomyelitis, notably by reducing T cell receptor (TCR)-induced activation of CD4⁺ T cells. Here, we demonstrate that transmethylation inhibition by a reversible S-adenosyl-l-homocysteine hydrolase inhibitor (DZ2002) led to immunosuppression by reducing TLR-, B cell receptor (BCR)- and TCR-induced activation of immune cells, most likely by blocking NF-κB activity. Moreover, prophylactic treatment with DZ2002 prevented lupus-like disease from developing in both BXSB and MRL-Fas^lpr mouse models. DZ2002 treatment initiated during active disease significantly improved outcomes in both in vivo models, suggesting methylation inhibition as a novel approach for the treatment of autoimmune/inflammatory diseases.

Original language	English
Pages (from-to)	133-143
Number of pages	11
Journal	Clinical Immunology
Volume	147
Issue number	2
DOIs	https://doi.org/10.1016/j.clim.2013.02.018
State	Published - May 2013
Externally published	Yes

Keywords

Lymphocytes
S-adenosyl-l-homocysteine hydrolase
Systemic lupus erythematosus
Toll-like receptors
Transmethylation

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.clim.2013.02.018

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title = "Critical role of transmethylation in TLR signaling and systemic lupus erythematosus",

abstract = "Post-translational protein modifications can play a significant role in immune cell signaling. Recently, we showed that inhibition of transmethylation curtails experimental autoimmune encephalomyelitis, notably by reducing T cell receptor (TCR)-induced activation of CD4+ T cells. Here, we demonstrate that transmethylation inhibition by a reversible S-adenosyl-l-homocysteine hydrolase inhibitor (DZ2002) led to immunosuppression by reducing TLR-, B cell receptor (BCR)- and TCR-induced activation of immune cells, most likely by blocking NF-κB activity. Moreover, prophylactic treatment with DZ2002 prevented lupus-like disease from developing in both BXSB and MRL-Faslpr mouse models. DZ2002 treatment initiated during active disease significantly improved outcomes in both in vivo models, suggesting methylation inhibition as a novel approach for the treatment of autoimmune/inflammatory diseases.",

keywords = "Lymphocytes, S-adenosyl-l-homocysteine hydrolase, Systemic lupus erythematosus, Toll-like receptors, Transmethylation",

author = "Virginie Tardif and Yulia Manenkova and Michael Berger and Kasper Hoebe and Zuo, {Jian Ping} and Chong Yuan and Kono, {Dwight H.} and Theofilopoulos, {Argyrios N.} and Lawson, {Brian R.}",

note = "Funding Information: This is manuscript number 23,014 from the Department of Immunology and Microbial Science of The Scripps Research Institute. We thank M. Kat Occhipinti and Miriam Bloom for the editorial assistance and Tannaz Hasnat for the excellent technical assistance. This work was supported in part by funding from the NIH .",

year = "2013",

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doi = "10.1016/j.clim.2013.02.018",

language = "الإنجليزيّة",

volume = "147",

pages = "133--143",

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T1 - Critical role of transmethylation in TLR signaling and systemic lupus erythematosus

AU - Tardif, Virginie

AU - Manenkova, Yulia

AU - Berger, Michael

AU - Hoebe, Kasper

AU - Zuo, Jian Ping

AU - Yuan, Chong

AU - Kono, Dwight H.

AU - Theofilopoulos, Argyrios N.

AU - Lawson, Brian R.

N1 - Funding Information: This is manuscript number 23,014 from the Department of Immunology and Microbial Science of The Scripps Research Institute. We thank M. Kat Occhipinti and Miriam Bloom for the editorial assistance and Tannaz Hasnat for the excellent technical assistance. This work was supported in part by funding from the NIH .

PY - 2013/5

Y1 - 2013/5

N2 - Post-translational protein modifications can play a significant role in immune cell signaling. Recently, we showed that inhibition of transmethylation curtails experimental autoimmune encephalomyelitis, notably by reducing T cell receptor (TCR)-induced activation of CD4+ T cells. Here, we demonstrate that transmethylation inhibition by a reversible S-adenosyl-l-homocysteine hydrolase inhibitor (DZ2002) led to immunosuppression by reducing TLR-, B cell receptor (BCR)- and TCR-induced activation of immune cells, most likely by blocking NF-κB activity. Moreover, prophylactic treatment with DZ2002 prevented lupus-like disease from developing in both BXSB and MRL-Faslpr mouse models. DZ2002 treatment initiated during active disease significantly improved outcomes in both in vivo models, suggesting methylation inhibition as a novel approach for the treatment of autoimmune/inflammatory diseases.

AB - Post-translational protein modifications can play a significant role in immune cell signaling. Recently, we showed that inhibition of transmethylation curtails experimental autoimmune encephalomyelitis, notably by reducing T cell receptor (TCR)-induced activation of CD4+ T cells. Here, we demonstrate that transmethylation inhibition by a reversible S-adenosyl-l-homocysteine hydrolase inhibitor (DZ2002) led to immunosuppression by reducing TLR-, B cell receptor (BCR)- and TCR-induced activation of immune cells, most likely by blocking NF-κB activity. Moreover, prophylactic treatment with DZ2002 prevented lupus-like disease from developing in both BXSB and MRL-Faslpr mouse models. DZ2002 treatment initiated during active disease significantly improved outcomes in both in vivo models, suggesting methylation inhibition as a novel approach for the treatment of autoimmune/inflammatory diseases.

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KW - S-adenosyl-l-homocysteine hydrolase

KW - Systemic lupus erythematosus

KW - Toll-like receptors

KW - Transmethylation

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DO - 10.1016/j.clim.2013.02.018

M3 - مقالة

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SN - 1521-6616

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SP - 133

EP - 143

JO - Clinical Immunology

JF - Clinical Immunology

IS - 2

ER -

Critical role of transmethylation in TLR signaling and systemic lupus erythematosus

Abstract

Keywords

All Science Journal Classification (ASJC) codes

UN SDGs

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