title: Glatiramer acetate attenuates the activation of CD4+T cells by modulating STAT1 and -3 signaling in glia.
abstract: Interactions between immune effector cells of the central nervous system appear to directly or indirectly influence the progress/regression of multiple sclerosis (MS). Here, we report that glial STAT1 and -3 are distinctively phosphorylated following the interaction of activated lymphocytes and glia, and this effect is significantly inhibited by glatiramer acetate (GA), a disease-modifying drug for MS. GA also reduces the activations of STAT1 and -3 by MS-associated stimuli such as IFNγ or LPS in primary glia, but not neurons. Experiments in IFNγ- and IFNγ receptor-deficient mice revealed that GA-induced inhibitions of STAT signaling are independent of IFNγ and its receptor. Interestingly, GA induces the expression levels of suppressor of cytokine signaling-1 and -3, representative negative regulators of STAT signaling in glia. We further found that GA attenuates the LPS-triggered enhancement of IL-2, a highly produced cytokine in patients with active MS, in CD4+T cells co-cultured with glia, but not in CD4+T cells alone. Collectively, these results provide that activation of glial STATs is an essential event in the interaction between glia and T cells, which is a possible underlying mechanism of GA action in MS. These findings provide an insight for the development of targeted therapies against MS.
authors.affiliation: Cancer Immunology Branch, National Cancer Center, Goyang, South Korea.|Dept.of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Ye-Hyeon
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Cancer Immunology Branch, National Cancer Center, Goyang, South Korea.
authors.forename: Sae-Bom
authors.initials: SB
authors.lastname: Jeon
authors.affiliation: Cancer Immunology Branch, National Cancer Center, Goyang, South Korea.
authors.forename: Chi Young
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Dept. of System Cancer Science, Graduate School of Cancer Science and Policy, Goyang, South Korea.
authors.forename: Eun-Ah
authors.initials: EA
authors.lastname: Goh
authors.affiliation: Radiation Medicine Branch, National Cancer Center, Goyang, South Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Dept. of System Cancer Science, Graduate School of Cancer Science and Policy, Goyang, South Korea.|Dept. of Neurology, National Cancer Center, Goyang, South Korea.
authors.forename: Ho Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Dept.of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Jaewhan
authors.initials: J
authors.lastname: Song
authors.affiliation: Cancer Immunology Branch, National Cancer Center, Goyang, South Korea.|Dept. of System Cancer Science, Graduate School of Cancer Science and Policy, Goyang, South Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D000068717:Glatiramer Acetate / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D016207:Cytokines; D000068717:Glatiramer Acetate; D007371:Interferon-gamma; D007376:Interleukin-2; D019000:Phosphotyrosine; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000096743:Interferon gamma Receptor