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Multiple sclerosis: modulation of toll-like receptor (TLR) expression by interferon-β includes upregulation of TLR7 in plasmacytoid dendritic cells.
PLoS One. 2013; 8(8):e70626.Plos

Abstract

Interferon-β is an established treatment for patients with multiple sclerosis (MS) but its mechanisms of action are not well understood. Viral infections are a known trigger of MS relapses. Toll-like receptors (TLRs) are key components of the innate immune system, which sense conserved structures of viruses and other pathogens. Effects of interferon-β on mRNA levels of all known human TLRs (TLR1-10) and the TLR adaptor molecule MyD88 were analyzed in peripheral blood mononuclear cells (PBMCs) of healthy donors by quantitative real-time PCR and by transcriptome analysis in PBMCs of 25 interferon-β-treated patients with relapsing-remitting MS. Regulation of TLR protein expression by interferon-β was investigated by flow cytometry of leukocyte subsets of healthy subjects and of untreated, interferon-β-, or glatiramer acetate-treated patients with MS. Interferon-β specifically upregulated mRNA expression of TLR3, TLR7, and MyD88 and downregulated TLR9 mRNA in PBMCs of healthy donors as well as in PBMCs of patients with MS. Plasmacytoid dendritic cells (pDCs) were identified as the major cell type responding to interferon-β with increased expression of TLR7 and MyD88 protein. In line with this, expression of TLR7 protein was increased in pDCs of interferon-β-treated, but not untreated or glatiramer acetate-treated patients with MS. Interferon-β-induced upregulation of TLR7 in pDCs is of functional relevance since pre-treatment of PBMCs with interferon-β resulted in a strongly increased production of interferon-α upon stimulation with the TLR7 agonist loxoribine. Flow cytometry confirmed pDCs as the cellular source of interferon-α production induced by activation of TLR7. Thus, upregulation of TLR7 in pDCs and a consequently increased activation of pDCs by TLR7 ligands represents a novel immunoregulatory mechanism of interferon-β. We hypothesize that this mechanism could contribute to a reduction of virus-triggered relapses in patients with MS.

Authors+Show Affiliations

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23950974

Citation

Derkow, Katja, et al. "Multiple Sclerosis: Modulation of Toll-like Receptor (TLR) Expression By Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells." PloS One, vol. 8, no. 8, 2013, pp. e70626.
Derkow K, Bauer JM, Hecker M, et al. Multiple sclerosis: modulation of toll-like receptor (TLR) expression by interferon-β includes upregulation of TLR7 in plasmacytoid dendritic cells. PLoS ONE. 2013;8(8):e70626.
Derkow, K., Bauer, J. M., Hecker, M., Paap, B. K., Thamilarasan, M., Koczan, D., Schott, E., Deuschle, K., Bellmann-Strobl, J., Paul, F., Zettl, U. K., Ruprecht, K., & Lehnardt, S. (2013). Multiple sclerosis: modulation of toll-like receptor (TLR) expression by interferon-β includes upregulation of TLR7 in plasmacytoid dendritic cells. PloS One, 8(8), e70626. https://doi.org/10.1371/journal.pone.0070626
Derkow K, et al. Multiple Sclerosis: Modulation of Toll-like Receptor (TLR) Expression By Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells. PLoS ONE. 2013;8(8):e70626. PubMed PMID: 23950974.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Multiple sclerosis: modulation of toll-like receptor (TLR) expression by interferon-β includes upregulation of TLR7 in plasmacytoid dendritic cells. AU - Derkow,Katja, AU - Bauer,Jakob M J, AU - Hecker,Michael, AU - Paap,Brigitte K, AU - Thamilarasan,Madhan, AU - Koczan,Dirk, AU - Schott,Eckart, AU - Deuschle,Katrin, AU - Bellmann-Strobl,Judith, AU - Paul,Friedemann, AU - Zettl,Uwe K, AU - Ruprecht,Klemens, AU - Lehnardt,Seija, Y1 - 2013/08/12/ PY - 2013/03/07/received PY - 2013/06/19/accepted PY - 2013/8/17/entrez PY - 2013/8/21/pubmed PY - 2014/3/7/medline SP - e70626 EP - e70626 JF - PloS one JO - PLoS ONE VL - 8 IS - 8 N2 - Interferon-β is an established treatment for patients with multiple sclerosis (MS) but its mechanisms of action are not well understood. Viral infections are a known trigger of MS relapses. Toll-like receptors (TLRs) are key components of the innate immune system, which sense conserved structures of viruses and other pathogens. Effects of interferon-β on mRNA levels of all known human TLRs (TLR1-10) and the TLR adaptor molecule MyD88 were analyzed in peripheral blood mononuclear cells (PBMCs) of healthy donors by quantitative real-time PCR and by transcriptome analysis in PBMCs of 25 interferon-β-treated patients with relapsing-remitting MS. Regulation of TLR protein expression by interferon-β was investigated by flow cytometry of leukocyte subsets of healthy subjects and of untreated, interferon-β-, or glatiramer acetate-treated patients with MS. Interferon-β specifically upregulated mRNA expression of TLR3, TLR7, and MyD88 and downregulated TLR9 mRNA in PBMCs of healthy donors as well as in PBMCs of patients with MS. Plasmacytoid dendritic cells (pDCs) were identified as the major cell type responding to interferon-β with increased expression of TLR7 and MyD88 protein. In line with this, expression of TLR7 protein was increased in pDCs of interferon-β-treated, but not untreated or glatiramer acetate-treated patients with MS. Interferon-β-induced upregulation of TLR7 in pDCs is of functional relevance since pre-treatment of PBMCs with interferon-β resulted in a strongly increased production of interferon-α upon stimulation with the TLR7 agonist loxoribine. Flow cytometry confirmed pDCs as the cellular source of interferon-α production induced by activation of TLR7. Thus, upregulation of TLR7 in pDCs and a consequently increased activation of pDCs by TLR7 ligands represents a novel immunoregulatory mechanism of interferon-β. We hypothesize that this mechanism could contribute to a reduction of virus-triggered relapses in patients with MS. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23950974/Multiple_sclerosis:_modulation_of_toll_like_receptor__TLR__expression_by_interferon_β_includes_upregulation_of_TLR7_in_plasmacytoid_dendritic_cells_ L2 - http://dx.plos.org/10.1371/journal.pone.0070626 DB - PRIME DP - Unbound Medicine ER -