Periplocoside E inhibits experimental allergic encephalomyelitis by suppressing interleukin 12-dependent CCR5 expression and interferon-gamma-dependent CXCR3 expression in T lymphocytes

• Published in: The Journal of pharmacology and experimental therapeutics 2006-09, Vol.318 (3), p.1153-1162
• Main Authors: Zhu, Yi-Na, Zhong, Xiang-Gen, Feng, Jia-Quan, Yang, Yi-Fu, Fu, Yun-Feng, Ni, Jia, Liu, Qun-Fang, Tang, Wei, Zhao, Wei-Min, Zuo, Jian-Ping
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Female; Gene Expression - drug effects; Immunosuppressive Agents - therapeutic use; Interferon-gamma - physiology; Interleukin-12 - physiology; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Myelin Proteins; Myelin-Associated Glycoprotein - immunology; Myelin-Oligodendrocyte Glycoprotein; Oligosaccharides - pharmacology; Oligosaccharides - therapeutic use; Pregnenes - pharmacology; Pregnenes - therapeutic use; Receptors, CCR5 - biosynthesis; Receptors, CCR5 - genetics; Receptors, Chemokine - biosynthesis; Receptors, Chemokine - genetics; Receptors, CXCR3; RNA, Messenger - analysis; Spinal Cord - metabolism; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.106.105445

Periplocoside E (PSE) was found to inhibit primary T-cell activation in our previous study. Now we examined the effect and mechanisms of PSE on the central nervous system (CNS) demyelination in experimental allergic encephalomyelitis (EAE). C57BL/6 mice immunized with myelin oligodendrocyte glyco-protein (MOG) were treated with PSE following immunization and continued throughout the study. The effect on the progression of EAE and other relevant parameters were assessed. PSE reduced the incidence and severity of EAE. Spinal cord histopathology analysis showed that the therapeutic effect of PSE was associated with reduced mononuclear cell infiltration and CNS inflammation. As reverse transcription-polymerase chain reaction analysis showed, PSE decreased the CD4(+), CD8(+), and CD11b(+) cell infiltration. T cells from lymph nodes of MOG-immunized mice expressed enhanced levels of CCR5 and CXCR3 mRNA compared with T cells from normal mice. However, CCR5 and CXCR3 expressions were suppressed in T cells from PSE-treated mice. In vitro study also showed PSE inhibited interferon (IFN)-gamma-dependent CXCR3 expression in T cells through suppressing T-cell receptor (TCR) ligation-induced IFN-gamma production, whereas it inhibited interleukin (IL)-12-dependent CCR5 expression through suppressing IL-12 reactivity in TCR-triggered T cells. As a result, the initial influx of T cells into CNS was inhibited in PSE-treated mice. The consequent activation of macrophages/microglia cells was inhibited in spinal cord from PSE-treated mice as determination of chemokine expressions (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10). Consistently, the secondary influx of CD4(+), CD8(+), and CD11b(+) cells was decreased in spinal cords from PSE-treated mice. These findings suggest the potential therapeutic effect of PSE on multiple sclerosis.