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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageAmerican English
Pages (from-to)133-143
Number of pages11
JournalClinical Immunology
Volume147
Issue number2
DOIs
StatePublished - May 2013
Externally publishedYes

Bibliographical 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 .

Keywords

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

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