scholarly journals Curcumin Modulates Macrophage Polarization Through the Inhibition of the Toll-Like Receptor 4 Expression and its Signaling Pathways

2015 ◽  
Vol 36 (2) ◽  
pp. 631-641 ◽  
Author(s):  
Yaoyao Zhou ◽  
Tiantian Zhang ◽  
Xiaofei Wang ◽  
Xiaowei Wei ◽  
Yizhu Chen ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Macrophage Polarization ◽  
Mitogen Activated Protein Kinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Acute Monocytic Leukemia ◽  
Therapeutic Effects ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
M1 Macrophage ◽  
Wide Range

Background: Curcumin, the active ingredient in curcuma rhizomes, has a wide range of therapeutic effects. However, its atheroprotective activity in human acute monocytic leukemia THP-1 cells remains unclear. We investigated the activity and molecular mechanism of action of curcumin in polarized macrophages. Methods: Phorbol myristate acetate (PMA)-treated THP-1 cells were differentiated to macrophages, which were further polarized to M1 cells by lipopolysaccharide (LPS; 1 µg/ml) and interferon (IFN)-γ (20 ng/ml) and treated with varying curcumin concentrations. [3H]thymidine (3H-TdR) incorporation assays were utilized to measure curcumin-induced growth inhibition. The expression of tumor necrosis factor-a (TNF-a), interleukin (IL-6), and IL-12B (p40) were measured by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Macrophage polarization and its mechanism were evaluated by flow cytometry and western blot. Additionally, toll-like receptor 4 (TLR4) small interfering RNA and mitogen-activated protein kinase (MAPK) inhibitors were used to further confirm the molecular mechanism of curcumin on macrophage polarization. Results: Curcumin dose-dependently inhibited M1 macrophage polarization and the production of TNF-a, IL-6, and IL-12B (p40). It also decreased TLR4 expression, which regulates M1 macrophage polarization. Furthermore, curcumin significantly inhibited the phosphorylation of ERK, JNK, p38, and nuclear factor (NF)-γB. In contrast, SiTLR4 in combination with p-JNK, p-ERK, and p-p38 inhibition reduced the effect of curcumin on polarization. Conclusions: Curcumin can modulate macrophage polarization through TLR4-mediated signaling pathway inhibition, indicating that its effect on macrophage polarization is related to its anti-inflammatory and atheroprotective effects. Our data suggest that curcumin could be used as a therapeutic agent in atherosclerosis.

scholarly journals The Therapeutic Effects of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells on Scleroderma

2021 ◽  
Author(s):  
Yue Yu ◽  
Liangliang Shen ◽  
Xiaoyun Xie ◽  
Jingjun Zhao ◽  
Miao Jiang
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
Human Umbilical Cord ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
M1 Macrophage

Abstract Background: Scleroderma is a multisystem disease in which tissue fibrosis is caused by inflammation and vascular damage. The mortality of scleroderma has remained high due to a lack of effective treatments. However, exosomes derived from human umbilical cord mesenchymal stem cells (HUMSCs)-Ex have been regarded as potential treatments for various autoimmune diseases, and may also act as candidates for treating scleroderma. Methods: Mice with scleroderma received a single 50 μg HUMSCs-Ex. HUMSCs-Ex was characterized using transmission electron microscopy, nanoparticle tracking analysis and nanoflow cytometry. The therapeutic efficacy was assessed using histopathology, immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay and western blot. Results: HUMSCs-Ex ameliorated the deposition of extracellular matrix and suppressed the epithelial-mesenchymal transition process, and the effects lasted at least three weeks. In addition, HUMSCs-Ex promoted M1 macrophage polarization and inhibited M2 macrophage polarization, leading to the restoration of the balance of M1/M2 macrophages. Conclusion: We investigated the potential antifibrotic and anti-inflammatory effects of HUMSCs-Ex in a bleomycin-induced mouse model of scleroderma. So HUMSCs-Ex could be considered as a candidate therapy for scleroderma.

scholarly journals Interleukin 26 Skews Macrophage Polarization Towards M1 Phenotype by Activating cJUN and the NF-κB Pathway

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 938
Author(s):  
Yi-Hsuan Lin ◽  
Yi-Hsun Wang ◽  
Yi-Jen Peng ◽  
Feng-Cheng Liu ◽  
Gu-Jiun Lin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
Macrophage Differentiation ◽  
Macrophage Cells ◽  
M1 Macrophage ◽  
Interleukin 26

Interleukin 26 (IL-26) is a new member of the IL-10 family that is highly expressed in rheumatoid arthritis (RA). However, the functions of IL-26 produced by macrophages in RA have not been elucidated. In the present work, we evaluated the effects and the mechanisms of IL-26 on M1 and M2 macrophage differentiation. Human or mouse macrophage cells were treated with lipopolysaccharides (LPS), interferon gamma (IFNγ), or IL-4 alone or concurrently treated with IL-26 to monitor M1 or M2 macrophage subtypes. The expression level of M1 or M2 macrophage genes was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The molecular mechanisms of downstream signaling activation during differentiation were investigated by immunoblotting assay. Our results found that IL-26 promoted macrophage cells from CD80+ M1 macrophage differentiation, not from the CD206+ M2 phenotype. The messenger RNA of M1-type macrophage markers tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) was up-regulated in the IL-26-treated group. Also, the M1-related proinflammatory cytokines TNFα and IL-6 were induced after IL-26 stimulation. Interestingly, IL-10, a cytokine marker of M2 macrophage, was also elevated after IL-26 stimulation. Moreover, the M1-like macrophage stimulated by IL-26 underwent cJUN, nuclear factor kappa B (NF-κB), and signal transducer and activator of transcription 1 (STAT1) activation. Our findings suggested the role of IL-26 in synovial macrophages of active rheumatoid arthritis and provided a new insight into IL-26 as a candidate therapeutic target in rheumatoid arthritis.

scholarly journals Eosinophil Activation by Toll-Like Receptor 4 Ligands Regulates Macrophage Polarization

2019 ◽  
Vol 7 ◽  
Author(s):  
Jiyoung Yoon ◽  
Han-Na Um ◽  
Jinsun Jang ◽  
Young-An Bae ◽  
Woo-Jae Park ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Eosinophil Activation

scholarly journals SalmonellaFimbrial Protein FimH Is Involved in Expression of Proinflammatory Cytokines in a Toll-Like Receptor 4-Dependent Manner

2019 ◽  
Vol 87 (3) ◽  
Author(s):  
Kei-ichi Uchiya ◽  
Yurie Kamimura ◽  
Ayumi Jusakon ◽  
Toshiaki Nikai
Keyword(s):  
Proinflammatory Cytokines ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Type 1 Fimbriae ◽  
Serovar Typhimurium

ABSTRACTType 1 fimbriae are proteinaceous filamentous structures present on bacterial surfaces and are mainly composed of the major fimbrial protein subunit FimA and the adhesive protein FimH, which is located at the tip of the fimbrial shaft. Here, we investigated the involvement of type 1 fimbriae in the expression of proinflammatory cytokines in macrophages infected withSalmonella entericaserovar Typhimurium. The level of interleukin-1β (IL-1β) mRNA was lower in macrophages infected withfimAorfimHmutant strains than in those infected with wild-typeSalmonella. Treatment of macrophages with purified recombinant FimH protein, but not FimA, resulted in the activation of the mitogen-activated protein kinase and nuclear factor κB signaling pathways, leading to the expression of not only IL-1β but also other proinflammatory cytokines, such as IL-6 and tumor necrosis factor alpha. However, FimH carrying an N-terminal region deletion or heat-treated FimH did not show such effects. The expression of FimH-induced IL-1β was inhibited by treatment with the Toll-like receptor 4 (TLR4) inhibitor TAK-242 but not by treatment with polymyxin B, a lipopolysaccharide antagonist. Furthermore, FimH treatment stimulated HEK293 cells expressing TLR4 and MD-2/CD14 but did not stimulate HEK293 cells expressing only TLR4. Collectively, FimH is a pathogen-associated molecular pattern ofS. entericaserovar Typhimurium that is recognized by TLR4 in the presence of MD-2 and CD14 and plays a significant role in the expression of proinflammatory cytokines inSalmonella-infected macrophages.

Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells

2011 ◽  
Vol 300 (5) ◽  
pp. H1743-H1752 ◽  
Author(s):  
Ying Wang ◽  
Ming Xiang Zhang ◽  
Xiao Meng ◽  
Fu Qiang Liu ◽  
Guang Sheng Yu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Umbilical Vein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Mapk Phosphorylation ◽  
Tlr4 Mrna

In the present study, we tested our hypothesis that atorvastatin exerts its anti-inflammation effect via suppressing LPS-induced rapid upregulation of Toll-like receptor 4 (TLR4) mRNA and its downstream p38, ERK, and NF-κB signaling pathways in human umbilical-vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). TLR4 mRNA expression and its downstream kinase activities induced by LPS alone or atorvastatin + LPS in endothelial cells were quantified using quantitative real-time PCR and enzyme-linked immunosorbent assay. Preincubation of LPS-stimulated endothelial cells with TLR4 siRNA was conducted to identify the target of the anti-inflammatory effects of atorvastatin. Atorvastatin incubation resulted in the reduction of LPS-induced TLR4 mRNA expression, ERK1/2 and P38 MAPK phosphorylation, and NF-κB binding activity. Pretreatment with MEK/ERK1/2 inhibitor PD98059 attenuated atorvastatin + LPS-induced NF-κB activity but had no effect on P38 MAPK phosphorylation. In contrast, pretreatment with P38 MAPK inhibitor SB203580 resulted in upregulation of atorvastatin + LPS-induced ERK1/2 phosphorylation but had no significant effects on NF-κB activity. On the other hand, blocking NF-κB with SN50 produced no effects on atorvastatin + LPS-induced ERK1/2 and P38 MAPK phosphorylation. Moreover, TLR4 gene silencing produced the same effects as the atorvastatin treatment. In conclusion, atorvastatin downregulated TLR4 mRNA expression by two distinct signaling pathways. First, atorvastatin stabilized Iκ-Bα, which directly inhibited NF-κB activation. Second, atorvastatin inactivated ERK phosphorylation, which indirectly inhibited NF-κB activation. Suppression of p38 MAPK by atorvastatin upregulates ERK but exerts no effect on NF-κB.

scholarly journals Endotoxin Tolerance Inhibits Lyn and c-Src Phosphorylation and Association with Toll-Like Receptor 4 but Increases Expression and Activity of Protein Phosphatases

2015 ◽  
Vol 8 (2) ◽  
pp. 171-184 ◽  
Author(s):  
Yanbao Xiong ◽  
Michael Murphy ◽  
Tissa T. Manavalan ◽  
Goutham Pattabiraman ◽  
Fu Qiu ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Phosphatase ◽  
Tyrosine Phosphatase ◽  
Endotoxin Tolerance ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Mitogen Activated Protein ◽  
Ptp 1B

Endotoxin tolerance protects the host by limiting excessive 'cytokine storm' during sepsis, but compromises the ability to counteract infections in septic shock survivors. It reprograms Toll-like receptor (TLR) 4 responses by attenuating the expression of proinflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators, but the mechanisms of reprogramming remain unclear. In this study, we demonstrate that the induction of endotoxin tolerance in human monocytes, THP-1 and MonoMac-6 cells inhibited lipopolysaccharide (LPS)-mediated phosphorylation of Lyn, c-Src and their recruitment to TLR4, but increased total protein phosphatase (PP) activity and the expression of protein tyrosine phosphatase (PTP) 1B, PP2A, PTP nonreceptor type (PTPN) 22 and mitogen-activated protein kinase phosphatase (MKP)-1. Chemical PP inhibitors, okadaic acid, dephostatin and cantharidic acid markedly decreased or completely abolished LPS tolerance, indicating the importance of phosphatases in endotoxin tolerization. Overexpression of PTPN22 decreased LPS-mediated nuclear factor (NF)-κB activation, p38 phosphorylation and CXCL8 gene expression, while PTPN22 ablation upregulated LPS-induced p65 NF-κB and p38 phosphorylation and the expression of TNF-a and pro-IL-1ß mRNA, indicating PTPN22 as an inhibitor of TLR4 signaling. Thus, LPS tolerance interferes with TLR4 signaling by inhibiting Lyn and c-Src phosphorylation and their recruitment to TLR4, while increasing the phosphatase activity and expression of PP2A, PTPN22, PTP1B and MKP1.

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