Leukemia Inhibitory Factor Inhibits T Helper 17 Cell Differentiation and Confers Treatment Effects of Neural Progenitor Cell Therapy in Autoimmune Disease

• Published in: Immunity (Cambridge, Mass.) Vol. 35; no. 2; pp. 273 - 284
• Main Authors: Cao, Wei, Yang, Yiqing, Wang, Zhengyi, Liu, Ailian, Fang, Lei, Wu, Fenglan, Hong, Jian, Shi, Yufang, Leung, Stewart, Dong, Chen, Zhang, Jingwu Z.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.08.2011; Elsevier Limited
• Subjects: Animals; Cell Differentiation; Cells, Cultured; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - therapy; Experiments; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene expression; Health sciences; Humans; Interferon-gamma - genetics; Interferon-gamma - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Leukemia Inhibitory Factor - metabolism; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis - immunology; Multiple Sclerosis - therapy; Nanocrystals; Neurons - immunology; Neurons - metabolism; Neurons - pathology; Neurons - transplantation; Pathogenesis; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stem Cell Transplantation; Stem cells; Stem Cells - immunology; Stem Cells - metabolism; Stem Cells - pathology; Studies; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - immunology; Suppressor of Cytokine Signaling Proteins - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - pathology
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2011.06.011

Neural progenitor cell (NPC) therapy is considered a promising treatment modality for multiple sclerosis (MS), potentially acting through neural repair. Here, we showed that intravenous administration of NPCs ameliorated experimental autoimmune encephalomyelitis (EAE) by selectively inhibiting pathogenic T helper 17 (Th17) cell differentiation. Leukemia inhibitory factor (LIF) produced by NPCs was responsible for the observed EAE suppression. Through the inducible LIF receptor expression, LIF inhibited the differentiation of Th17 cells in EAE mice and that from MS subjects. At the molecular level, LIF exerted an opposing effect on interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation required for Th17 cell differentiation by triggering a signaling cascade that activated extracellular signal-regulated MAP kinase (ERK) and upregulated suppressor of cytokine signaling 3 (SOCS3) expression. This study reveals a critical role for LIF in regulating Th17 cell differentiation and provides insights into the mechanisms of action of NPC therapy in MS. ► NPCs ameliorate EAE through the selective inhibition of Th17 cells ► Secretion of LIF is responsible for the inhibition of Th17 cells and EAE by NPCs ► LIF upregulates SOCS3 via the ERK pathway to suppress STAT3 activity in Th17 cells