STAT5 mediates antiapoptotic effects of methylprednisolone on oligodendrocytes.
Methylprednisolone (MP), a synthetic glucocorticoid agonist, is widely used for the clinical therapy of white matter diseases in the nervous system, such as spinal cord injury and multiple sclerosis. In addition to its potent anti-inflammatory and antioxidant properties, we recently discovered a selective antiapoptotic effect of MP on oligodendrocytes via the activation of the glucocorticoid receptor (GR) and the upregulation of bcl-X(L), a splicing isoform of the bcl-x gene. Based on published findings of the functional interactions between GR and STAT5, a transcription factor from the family of signal transducers and activators of transcription (STAT), we examined whether the glucocorticoid signaling pathway interacts with STAT5 to upregulate bcl-X(L) and protect oligodendrocytes. We show herein that (1) the GR and STAT5 complex is present on the STAT5-binding site of the bcl-x promoter region in oligodendrocytes; (2) the overexpression of an activated form of STAT5 prevents alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced oligodendrocyte cell death; and (3) this prevention is lost when the STAT5 gene is knocked down. Thus, our results provide one molecular mechanism underlying the postinjury protective effects of oligodendrocytes by stress hormones.
Xu
Jan
J
Department of Neurology, Center for Aging, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Chen
Shawei
S
Chen
Hong
H
Xiao
Qingli
Q
Hsu
Chung Y
CY
Michael
Drew
D
Bao
Jianxin
J
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D008775:Methylprednisolone / Q000494:pharmacology*; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism
C494813:Bcl2l1 protein, rat; D018696:Neuroprotective Agents; D011965:Receptors, Glucocorticoid; D050799:STAT5 Transcription Factor; C494094:Stat5a protein, rat; D051020:bcl-X Protein; D008775:Methylprednisolone