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Forschungsdatenbank PMU-SQQUID

Inhibition of Smad7, a negative regulator of TGF-beta signaling, suppresses autoimmune encephalomyelitis.
Kleiter, I; Pedré, X; Mueller, AM; Poeschl, P; Couillard-Despres, S; Spruss, T; Bogdahn, U; Giegerich, G; Steinbrecher, A;
J Neuroimmunol. 2007; 187(1-2):61-73
Originalarbeiten (Zeitschrift)

PMU-Autor/inn/en

Couillard-Després Sébastien

Abstract

We studied the role of the Transforming growth factor (TGF)-beta signaling antagonist Smad7 in autoimmune central nervous system (CNS) inflammation by using specific antisense oligonucleotides (Smad7-as). Elevated Smad7 protein expression was found in the spinal cord of SJL/J mice and DA rats with experimental autoimmune encephalomyelitis (EAE) and in effector T cells upon antigen stimulation. Smad7-as specifically decreased Smad7 mRNA and protein in cell lines and in ex-vivo-treated primary mouse lymph node cells (LNC). LNC exposed to Smad7-as during secondary activation showed reduced proliferation and encephalitogenicity. After systemic administration, Smad7-as ameliorated clinical signs of active and adoptively transferred EAE, diminished CNS inflammation, and reduced Smad7 protein levels in the brain. Smad7-as was found to be incorporated by peritoneal macrophages as well as by cells of the liver, kidneys, and peripheral lymph nodes. Importantly, Smad7-as treatment was not toxic and did not increase extracellular matrix formation. Smad7 inhibition thus represents a novel systemic treatment strategy for autommume CNS inflammation, targeting TGF-beta signaling without TGF-beta-associated toxicity. (c) 2007 Elsevier B.V. All rights reserved.


Useful keywords (using NLM MeSH Indexing)

Adoptive Transfer/methods

Animals

Cell Proliferation/drug effects

Cells, Cultured

Disease Models, Animal

Encephalomyelitis, Autoimmune, Experimental/chemically induced

Encephalomyelitis, Autoimmune, Experimental/metabolism*

Encephalomyelitis, Autoimmune, Experimental/therapy*

Female

Gene Expression Regulation/drug effects

Lymphocytes/drug effects

Lymphocytes/metabolism

Mice

Mice, Inbred Strains

Oligonucleotides, Antisense/pharmacology

Oligonucleotides, Antisense/therapeutic use

RNA, Messenger/biosynthesis

Rats

Reverse Transcriptase Polymerase Chain Reaction/methods

Signal Transduction/drug effects

Signal Transduction/physiology*

Smad7 Protein/chemistry

Smad7 Protein/metabolism*

Thionucleotides/pharmacology

Thionucleotides/therapeutic use

Time Factors

Transforming Growth Factor beta/physiology*


Find related publications in this database (Keywords)

autoimmunity
inflammation
T cell
TGF-beta
Smad7
antisense oligonucleotide