IL-10 promotes neuronal survival following spinal cord injury.
We have previously reported that the anti-inflammatory cytokine IL-10 induces a number of signaling cascades through the IL-10 receptor in spinal cord neurons in vitro to activate NF-kappaB transcription Bcl-2 and Bcl-x(L) and that, after exposure to glutamate IL-10, blocks cytochrome c release and caspase cleavage. In the current study we used a herpes simplex virus (HSV)-based vector to express IL-10 in spinal cord in vivo. Injection of the vector 30 minutes after lateral hemisection injury resulted in increased neuronal survival in the anterior quadrant of the spinal cord and improved motor function up to 6 weeks after injury, that correlated with translocation of p50 and p65 NF-kappaB to the nucleus and increased expression of Bcl-2 and Bcl-x(L) in anterior quadrant neurons. Inhibition of cytochrome c release and caspase 3 cleavage was seen in homogenates of injured spinal cord treated by the IL-10 vector. Taken together with in vitro studies that demonstrate direct neuroprotective effects of IL-10 acting through the neuronal IL-10 receptor, these results suggest that IL-10 may provide direct neuroprotective effects in spinal cord injury separate from and in addition to the known anti-inflammatory effects and point to the possibility that IL-10 delivery by gene transfer may be a useful adjunctive therapy for spinal cord injury.
Zhou
Zhigang
Z
Department of Neurology, University of Michigan and Ann Arbor VA Healthcare System, 5027 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
Peng
Xiangmin
X
Insolera
Ryan
R
Fink
David J
DJ
Mata
Marina
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000494:pharmacology* / Q000627:therapeutic use; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018139:Simplexvirus / Q000235:genetics; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D051017:Apoptosis Regulatory Proteins; D053701:Receptors, Interleukin-10; D016753:Interleukin-10