Regulatory properties of copolymer I in Th17 differentiation by altering STAT3 phosphorylation.
Th17 and Th1 play an important role in multiple sclerosis for which copolymer I (COP-I) is a treatment option. We described here that the treatment effect of COP-I correlated with its unique regulatory properties on differentiation and survival of Th17 in experimental autoimmune encephalomyelitis mice, which was mediated through down-regulation of STAT3 phosphorylation. The effect of COP-I on Th17 differentiation required CD14(+) monocytes through IL-6 signaling as a key mediator to regulate STAT3 phosphorylation and subsequent RORgammat expression in Th17 cells. The observed effect was markedly dampened when monocytes were genetically deficient for IL-6. Similar regulatory properties of COP-I were demonstrated in human Th17 differentiation. The study revealed the differential regulatory roles and the novel mechanism of action of COP-I chiefly responsible for its treatment efficacy in experimental autoimmune encephalomyelitis and multiple sclerosis.
Chen
Chunhua
C
Institute of Health Sciences, Shanghai JiaoTong University School of Medicine, China.
Liu
Xuebin
X
Wan
Bing
B
Zhang
Jingwu Z
JZ
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007279:Injections, Subcutaneous; D020381:Interleukin-17 / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
C508717:IL17A protein, human; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010455:Peptides; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C021759:(T,G)-A-L