Inhibition of Smad7, a negative regulator of TGF-beta signaling, suppresses autoimmune encephalomyelitis.
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 autoimmune CNS inflammation, targeting TGF-beta signaling without TGF-beta-associated toxicity.
Kleiter
Ingo
I
Department of Neurology, University of Regensburg, Universitaetsstr. 84, 93053 Regensburg, Germany.
Pedré
Xiomara
X
Mueller
André M
AM
Poeschl
Peter
P
Couillard-Despres
Sebastien
S
Spruss
Thilo
T
Bogdahn
Ulrich
U
Giegerich
Gerhard
G
Steinbrecher
Andreas
A
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051906:Smad7 Protein / Q000737:chemistry / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D013873:Thionucleotides; D016212:Transforming Growth Factor beta