A1.7 The regulation of human in vitro TH17 cell differentiation

2015 ◽  
Vol 74 (Suppl 1) ◽  
pp. A3.1-A3
Author(s):  
E Baricza ◽  
E Lajkó ◽  
L Kőhidai ◽  
B Molnár-Érsek ◽  
N Marton ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cell Differentiation

scholarly journals Soufeng sanjie formula alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Di Hua ◽  
Jie Yang ◽  
Qinghai Meng ◽  
Yuanyuan Ling ◽  
Qin Wei ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Lymph Nodes ◽  
Inflammatory Cytokines ◽  
Th17 Cell ◽  
Collagen Induced Arthritis ◽  
Expression Levels ◽  
Th17 Cell Differentiation ◽  
Spleen And Lymph Nodes ◽  
Seed Coats

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch), scorpion (dried body of Buthus martensii Karsch), astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge), and black soybean seed coats (seed coats of Glycine max (L.) Merr), is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remains unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice. Methods For in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/day) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 days, degree of ankle joint destruction and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Moreover, the expression levels of retinoic acid receptor-related orphan nuclear receptor (ROR) γt and phosphorylated STAT3 (pSTAT3, Tyr705) in the spleen were detected by immunohistochemistry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in CD4+ T cells under Th17 polarization conditions. Results SF decreased the arthritis score, ameliorated paw swelling, and reduced cartilage loss in the joint of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG in sera of CIA mice. SF decreased the levels of inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 both in the sera and the joint of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. SF also reduced the expression levels of ROR γt and pSTAT3 (Tyr705) in the spleen of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, IL-17A, and pSTAT3 (Tyr705) under Th17 polarization conditions. Conclusions Our results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.

scholarly journals Soufeng Sanjie Formula Alleviates Collagen-induced Arthritis in Mice by Inhibiting Th17 Cell Differentiation

2021 ◽  
Author(s):  
Di Hua ◽  
Jie Yang ◽  
Qinghai Meng ◽  
Yuanyuan Ling ◽  
Qin Wei ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Lymph Nodes ◽  
Inflammatory Cytokines ◽  
Th17 Cell ◽  
Soybean Seed ◽  
Collagen Induced Arthritis ◽  
Th17 Cell Differentiation ◽  
Spleen And Lymph Nodes ◽  
Seed Coats

Abstract Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch), scorpion (dried body of Buthus martensii Karsch), astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge), and black soybean seed coats (seed coats of Glycine max (L.) Merr), and is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remain unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice.Methods: For in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/d) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 d, degree of ankle joint inflammatory infiltration and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in Th17 polarization.Results: SF decreased the arthritis score, ameliorated paw swelling, and reduced synovial hyperplasia in the joints of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG and inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 in the sera of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, and Il-17A under Th17 polarization conditions.Conclusions: Our results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.

scholarly journals PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Luis Eduardo Alves Damasceno ◽  
Douglas Silva Prado ◽  
Flavio Protasio Veras ◽  
Miriam M. Fonseca ◽  
Juliana E. Toller-Kawahisa ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Glycolytic Enzyme ◽  
Metabolic Reprogramming ◽  
Fine Tuning ◽  
Autoimmune Inflammation ◽  
Th17 Cell Differentiation ◽  
Key Factor

Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell–specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell–mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation.

scholarly journals CD147 Is Essential for the Development of Psoriasis via the Induction of Th17 Cell Differentiation

2021 ◽  
Vol 23 (1) ◽  
pp. 177
Author(s):  
Aoi Okubo ◽  
Youhei Uchida ◽  
Yuko Higashi ◽  
Takuya Sato ◽  
Youichi Ogawa ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Transmembrane Protein ◽  
Immunoglobulin Superfamily ◽  
Monocarboxylate Transporters ◽  
Th17 Cell Differentiation

Th17 cells play an important role in psoriasis. The differentiation of naïve CD4+ T cells into Th17 cells depends on glycolysis as the energy source. CD147/basigin, an integral transmembrane protein belonging to the immunoglobulin superfamily, regulates glycolysis in association with monocarboxylate transporters (MCTs)-1 and -4 in cancer cells and T cells. We examined whether CD147/basigin is involved in the pathogenesis of psoriasis in humans and psoriasis-model mice. The serum level of CD147 was increased in patients with psoriasis, and the expression of CD147 and MCT-1 was elevated in their dermal CD4+ RORγt+ T cells. In vitro, the potential of naïve CD4+ T cells to differentiate into Th17 cells was abrogated in CD147−/− T cells. Imiquimod (IMQ)-induced psoriatic dermatitis was significantly milder in CD147−/− mice and bone marrow chimeric mice lacking CD147 in the hematopoietic cells of myeloid lineage. These findings demonstrate that CD147 is essential for the development of psoriasis via the induction of Th17 cell differentiation.

scholarly journals Natural killer-like B cells promote Th17 cell differentiation and exacerbate rheumatoid arthritis

2021 ◽  
Author(s):  
Ping Wang ◽  
Jing Song ◽  
Mingxin Bai ◽  
Xi Zheng ◽  
Yang Xie ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Disease Progression ◽  
Natural Killer ◽  
Th17 Cell ◽  
Cell Subset ◽  
Th17 Cell Differentiation

B cells are important participants in the pathogenesis of rheumatoid arthritis (RA). Besides classical B cells, novel B cell subsets are continually to be identified in recent years. Natural killer-like B (NKB) cells, a newly recognized B cell subset, are proved to be actively involved in the anti-infection immunity. However, their role in RA and the potential mechanism remain elusive. Here, we showed that NKB cells were expanded dramatically in collagen-induced arthritis (CIA) mice, demonstrating dynamic changes during the disease progression. These cells promoted CD4+ effector T cell proliferation and Th17 cell differentiation in vitro, while adoptive transfer of these cells exacerbated the arthritis severity of CIA mice. RNA Sequencing revealed that NKB cells displayed distinct differential gene expression profile under RA circumstance, potential perpetuating the disease progression. Moreover, the frequencies of NKB cells were significantly increased in RA patients, positively correlated with the clinical and immunological features. After effective therapy, these cells could be recovered to normal levels. Taken together, our results preliminarily revealed the pathogenic role of NKB cells in RA by promoting Th17 proinflammatory responses. Targeting these cells might provide potential therapeutic strategies for this persistent disease.

Mesenchymal Stromal Cells Derived From Bone Marrow of Chronic Lymphocytic Leukemia Patients Promote Th17 Cell Differentiation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2414-2414
Author(s):  
Wei Ding ◽  
Traci Sassoon ◽  
Justin Boysen ◽  
Neil E. Kay
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cytokine Production ◽  
Normal Subjects ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Cd4 Cells ◽  
Th17 Cell Differentiation

Abstract Abstract 2414 Background: Mesenchymal stromal cells (MSC) derived from normal subjects are known to have immunosuppressive capacity by virtue of inhibiting T- and B-cell activation. A novel subset of T cells, Th17, plays an important role in inflammation and autoimmunity. A recent report demonstrated that normal MSC ameliorates experimental autoimmune encephalomyelitis by inhibiting CD4+ Th17 cells in a chemokine ligand 2-dependent manner (J Immunol. 2009, 182: 5994). It remains unknown if MSC derived from leukemic or cancer patients play a role in Th17 cell differentiation. In particular this would be of interest to study in B-Chronic Lymphocytic Leukemia (CLL) where immunosuppression is evident even in early stage disease. Methods: MSC derived from bone marrow of CLL patients or normal subjects were expanded in vitro as previously described by us (Br J Haematol. 2009, 147:471). CD4+ cells positively selected from normal peripheral blood mononuclear cells were co-cultured with either CLL MSC or normal MSC at a ratio of 50:1 for 3 days with stimulation via CD3/CD28 beads, as well as interleukin-1β (IL-1β; 50 ng/ml). Then phorbol 12-myristate 13-acetate (50 ng/ml) and ionomycin (500 ng/ml) were introduced into the co-culture for 5 hrs in the presence of brefeldin A. Subsequently, cells were stained with CD4-phycoerythrin (PE) and IL-17-Alexa647 using intracellular flow to analyze the percent expression of IL-17 in CD4 + cells. Cytokine production from both CLL MSC and normal MSC as secreted into culture medium (CM) were tested using a commercial multiplex cytokine array (Invitrogen, CA). This array measures the level of 30 different cytokines. Results: Positively selected CD4+ cells from peripheral blood of normal donors contain minimal percentages of Th17 cells (range: 0.48–0.71%). IL-1β stimulation induced increased IL-17 expression (range: 1.05–1.12%). Co-culture of CLL MSC with CD4+ cells induced significantly increased IL-17 expression in the CD4+ T cells (range: 1.16–1.32%). The promoting effect of CLL MSC on these Th17 cells appeared to be mediated by direct contact since the CM of CLL MSC was not able to induce increased IL-17 expression (mean = 0.66%) to a similar level as direct co-culture. When IL-1b was used to stimulate Th17 cell differentiation from CD4+ cells, CLL MSC were able to further promote the level of Th17 cell differentiation (range: 2.01–2.63%), indicating synergistic function for CLL MSC with IL-1β. This latter finding again appeared to be more pronounced for CLL MSC as normal MSC with IL-1β was not able to promote Th17 cell differentiation to a similar degree. To further investigate the mechanism of CLL MSC on Th17 cell differentiation, we assessed the cytokine production for resting CLL MSC and normal MSC compared to cytokine production of CLL and normal MSC stimulated with IL-17. The data from multiplex cytokine arrays revealed that the cytokine profiles were not different between resting CLL and normal MSC; however, when MSC were stimulated with IL-17, there were significant differences between CLL and normal MSC in terms of IL-6 and MCP-1 production (IL-6, CLL vs. normal, 957.9 ± 98 vs. 554.2 ± 92.3 pg/ml, p = 0.01; MCP-1, CLL vs. normal, 787.7 ± 166.9 vs. 330.2 ± 116.5 pg/ml, p = 0.04, n = 7). Since both IL-6 and MCP-1 have been demonstrated to play important roles in Th17 differentiation, we are conducting further studies to dissect the mechanism of CLL MSC in the promotion of Th17 cell differentiation. Conclusions: These results indicate that MSC derived from CLL patients promotes Th17 cell differentiation in vitro, which is in contrast to the previous published suppressive role of normal MSC on Th17 cell differentiation. Recent findings have indeed demonstrated that CLL patients do have high percentage of Th17 cells (Cancer Res. 2009. 69: 5922) when compared to other lymphoproliferative diseases. Given this data we believe that CLL MSC are intrinsically different from normal MSC in terms of immune regulation and cytokine production. This may occur as a result of the bi-directional activation that we found to be present between MSC and CLL leukemic cells (Br. J Haematol. 2009. 147:471). In total, our findings demonstrated that the dynamic interactions between the CLL leukemic cells and MSC appear to influence the Th 17 cell levels. This is of biological and clinical interest in that Th17 cells have the potential to regulate the immune environment to favor tumor proliferation and progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and interleukin-6 production

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1005-1015 ◽  
Author(s):  
Chongyun Fang ◽  
Xinhua Zhang ◽  
Takashi Miwa ◽  
Wen-Chao Song
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Transfer Model ◽  
T Helper ◽  
T Helper 17 ◽  
C5a Receptor ◽  
Serum Factors ◽  
Th17 Cell Differentiation

Toll-like receptors (TLRs) and complement are 2 major components of innate immunity that provide a first-line host defense and shape the adaptive immune responses. We show here that coincidental activation of complement and several TLRs in mice led to the synergistic production of serum factors that promoted T-helper cell 17 (Th17) differentiation from anti-CD3/CD28 or antigen-stimulated T cells. Although multiple TLR-triggered cytokines were regulated by complement, Th17 cell–promoting activity in the serum was correlated with interleukin (IL)–6 induction, and antibody neutralization of IL-6 abrogated the complement effect. By using both in vitro and in vivo approaches, we examined in more detail the mechanism and physiologic implication of complement/TLR4 interaction on Th17-cell differentiation. We found that the complement effect required C5a receptor, was evident at physiologically relevant levels of C5a, and could be demonstrated in cultured peritoneal macrophages as well as in the setting of antigen immunization. Importantly, despite an inhibitory effect of complement on IL-23 production, complement-promoted Th17 cells were functionally competent in causing autoimmunity in an adoptive transfer model of experimental autoimmune encephalomyelitis. Collectively, these data establish a link between complement/TLR interaction and Th17-cell differentiation and provide new insight into the mechanism of action of complement in autoimmunity.

AB0023 The Regulation of Human In Vitro Th17 Cell Differentiation by Cytokines

2016 ◽  
Vol 75 (Suppl 2) ◽  
pp. 904.3-905
Author(s):  
E. Baricza ◽  
E. Lajkό ◽  
L. Kőhidai ◽  
B. Molnár-Έrsek ◽  
N. Marton ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cell Differentiation

scholarly journals PTEN drives Th17 cell differentiation by preventing IL-2 production

2017 ◽  
Vol 214 (11) ◽  
pp. 3381-3398 ◽  
Author(s):  
Hyeong Su Kim ◽  
Sung Woong Jang ◽  
Wonyong Lee ◽  
Kiwan Kim ◽  
Hyogon Sohn ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Cell Subset ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
Stat3 Phosphorylation ◽  
Pten Deletion ◽  
Key Factor ◽  
Phosphatase And Tensin Homologue

T helper 17 (Th17) cells are a CD4+ T cell subset that produces IL-17A to mediate inflammation and autoimmunity. IL-2 inhibits Th17 cell differentiation. However, the mechanism by which IL-2 is suppressed during Th17 cell differentiation remains unclear. Here, we show that phosphatase and tensin homologue (PTEN) is a key factor that regulates Th17 cell differentiation by suppressing IL-2 production. Th17-specific Pten deletion (Ptenfl/flIl17acre) impairs Th17 cell differentiation in vitro and ameliorated symptoms of experimental autoimmune encephalomyelitis (EAE), a model of Th17-mediated autoimmune disease. Mechanistically, Pten deficiency up-regulates IL-2 and phosphorylation of STAT5, but reduces STAT3 phosphorylation, thereby inhibiting Th17 cell differentiation. PTEN inhibitors block Th17 cell differentiation in vitro and in the EAE model. Thus, PTEN plays a key role in Th17 cell differentiation by blocking IL-2 expression.

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