title: Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T Cells in MS.
abstract: IFN-beta currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-beta on the regulation of OPN and IL-17 in MS patients. We found that IFN-beta used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4(+) T-cell level. In addition, IFN-beta inhibited the production of IL-17 and IL-21 in CD4(+) T cells. It has been described that IFN-beta suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-beta also acted directly on the CD4(+) T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-beta to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN(+) and IL-17(+) cells decreased in IFN-beta-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-beta treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-beta treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-beta in the treatment of MS.
authors: Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Meiyue
authors: M
authors: Chen
authors: Guangjie
authors: G
authors: Chen
authors: Hong
authors: H
authors: Nie
authors: Xin
authors: X
authors: Zhang
authors: Xiaoyin
authors: X
authors: Niu
authors: Ying C Q
authors: YC
authors: Zang
authors: Sheri M
authors: SM
authors: Skinner
authors: Jingwu Z
authors: JZ
authors: Zhang
authors: James M
authors: JM
authors: Killian
authors: Jian
authors: J
authors: Hong
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000819:agonists / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D006023:Glycoproteins; D020381:Interleukin-17; D007378:Interleukins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C445081:myelin oligodendrocyte glycoprotein (35-55); D053495:Osteopontin; D016899:Interferon-beta; D000098546:Interleukin-21