Gypenoside AttenuatesβAmyloid-Induced Inflammation in N9 Microglial Cells via SOCS1 Signaling

Reducingβamyloid- (Aβ-) induced microglial activation is believed to be effective in treating Alzheimer’s disease (AD). Microglia can be activated into classic activated state (M1 state) or alternative activated state (M2 state), and the former is harmful; in contrast, the latter is beneficial. Gypenoside (GP) is the major bioactive constituent ofGynostemma pentaphyllum, a traditional Chinese herb medicine. In this study, we hypothesized that GP attenuates Aβ-induced microglial activation by ameliorating microglial M1/M2 states, and the process may be mediated by suppressor of cell signaling protein 1 (SOCS1). In this study, we found that Aβexposure increased the levels of microglial M1 markers, including iNOS expression, tumor necrosis factorα(TNF-α), interleukin 1β(IL-1β), and IL-6 releases, and coadministration of GP reversed the increase of M1 markers and enhanced the levels of M2 markers, including arginase-1 (Arg-1) expression, IL-10, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF) releases in the Aβ-treated microglial cells. SOCS1-siRNA, however, significantly abolished the GP-induced effects on the levels of microglial M1 and M2 markers. These findings indicated that GP attenuates Aβ-induced microglial activation by ameliorating M1/M2 states, and the process may be mediated by SOCS1.

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SOCS1 Mediates Berberine-Induced Amelioration of Microglial Activated States in N9 Microglia Exposed to β Amyloid

BioMed Research International ◽

10.1155/2021/9311855 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Qi Guo ◽

Chen Wang ◽

Xiaorong Xue ◽

Bin Hu ◽

He Bao

Keyword(s):

Neurotrophic Factor ◽

Microglial Activation ◽

Microglial Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Cytokine Signaling ◽

Arginase 1 ◽

Inos Protein Expression ◽

Activated State ◽

Β Amyloid ◽

Factor Α

Attenuating β amyloid- (Aβ-) induced microglial activation is considered to be effective in treating Alzheimer’s disease (AD). Berberine (BBR) can reduce microglial activation in Aβ-treated microglial cells; the mechanism, however, is still illusive. Silencing of cytokine signaling factor 1 (SOCS1) is the primary regulator of many cytokines involved in immune reactions, whose upregulation can reverse the activation of microglial cells. Microglia could be activated into two different statuses, classic activated state (M1 state) and alternative activated state (M2 state), and M1 state is harmful, but M2 is beneficial. In the present study, N9 microglial cells were exposed to Aβ to imitate microglial activation in AD. And Western blot and immunocytochemistry were taken to observe inducible nitric oxide synthase (iNOS), Arginase-1 (Arg-1), and SOCS1 expressions, and the enzyme-linked immunosorbent assay (ELISA) was used to measure inflammatory and neurotrophic factor release. Compared with the normal cultured control cells, Aβ exposure markedly increased the level of microglial M1 state markers ( P < 0.05 ), including iNOS protein expression, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 releases, and BBR administration upregulated SOSC1 expression and the level of microglial M2 state markers ( P < 0.05 ), such as Arg-1 expression, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF) releases, downregulating the SOCS1 expression by using siRNA, however, significantly reversed the BBR-induced effects on microglial M1 and M2 state markers and SOCS1 expression ( P < 0.05 ). These findings indicated that BBR can inhibit Aβ-induced microglial activation via modulating the microglial M1/M2 activated state, and SOCS1 mediates the process.

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Cannabinoid CB2 Receptor Mediates Nicotine-Induced Anti-Inflammation in N9 Microglial Cells Exposed toβAmyloid via Protein Kinase C

Mediators of Inflammation ◽

10.1155/2016/4854378 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Ji Jia ◽

Jie Peng ◽

Zhaoju Li ◽

Youping Wu ◽

Qunlin Wu ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Microglial Activation ◽

Microglial Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Cb2 Receptor ◽

Arginase 1 ◽

Kinase C ◽

Activated State ◽

Anti Inflammation

Background. Reducingβamyloid- (Aβ-) induced microglial activation is considered to be effective in treating Alzheimer’s disease (AD). Nicotine attenuates Aβ-induced microglial activation; the mechanism, however, is still elusive. Microglia could be activated into classic activated state (M1 state) or alternative activated state (M2 state); the former is cytotoxic and the latter is neurotrophic. In this investigation, we hypothesized that nicotine attenuates Aβ-induced microglial activation by shifting microglial M1 to M2 state, and cannabinoid CB2 receptor and protein kinase C mediate the process.Methods. We used Aβ1–42 to activate N9 microglial cells and observed nicotine-induced effects on microglial M1 and M2 biomarkers by using western blot, immunocytochemistry, and enzyme-linked immunosorbent assay (ELISA).Results. We found that nicotine reduced the levels of M1 state markers, including inducible nitric oxide synthase (iNOS) expression and tumor necrosis factorα(TNF-α) and interleukin- (IL-) 6 releases; meanwhile, it increased the levels of M2 state markers, including arginase-1 (Arg-1) expression and brain-derived neurotrophic factor (BDNF) release, in the Aβ-stimulated microglia. Coadministration of cannabinoid CB2 receptor antagonist or protein kinase C (PKC) inhibitor partially abolished the nicotine-induced effects.Conclusion. These findings indicated that cannabinoid CB2 receptor mediates nicotine-induced anti-inflammation in microglia exposed to Aβvia PKC.

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Regulation of rabbit acute phase protein biosynthesis by monokines

Biochemical Journal ◽

10.1042/bj2530851 ◽

1988 ◽

Vol 253 (3) ◽

pp. 851-857 ◽

Cited By ~ 61

Author(s):

A Mackiewicz ◽

M K Ganapathi ◽

D Schultz ◽

D Samols ◽

J Reese ◽

...

Keyword(s):

Acute Phase ◽

Serum Amyloid A ◽

Interleukin 1 ◽

Serum Amyloid ◽

C Reactive Protein ◽

Reactive Protein ◽

Amyloid A ◽

Primary Hepatocyte Cultures ◽

Dose Dependent ◽

Necrosis Factor

We defined the acute phase behaviour of a number of rabbit plasma proteins in studies (in vivo) and studied the effects of monokine preparations on their synthesis by rabbit primary hepatocyte cultures. Following turpentine injection, increased serum levels of C-reactive protein, serum amyloid A protein, haptoglobin, ceruloplasmin, and decreased concentrations of albumin were observed. In contrast to what is observed in man, concentrations of alpha 2-macroglobulin and transferrin were increased. Co-culture of primary hepatocyte cultures with lipopolysaccharide-activated human peripheral blood monocytes or incubation with conditioned medium prepared from lipopolysaccharide-activated human or rabbit monocytes resulted in dose-dependent induction of serum amyloid A, haptoglobin, ceruloplasmin and transferrin and depression of albumin synthesis, while C-reactive protein synthesis and mRNA levels remained unchanged. A variety of interleukin-1 preparations induced dose-dependent increases in the synthesis and secretion of serum amyloid A, haptoglobin, ceruloplasmin and transferrin and decreased albumin synthesis. Human recombinant tumour necrosis factor (cachectin) induced a dose-dependent increase in synthesis of haptoglobin and ceruloplasmin. In general, human interleukin-1 was more potent than mouse interleukin-1 and tumour necrosis factor. None of the monokines we studied had an effect on C-reactive protein synthesis or mRNA levels. These data confirm that C-reactive protein, serum amyloid A, haptoglobin and ceruloplasmin display acute phase behaviour in the rabbit, and demonstrate that, in contrast to their behaviour in man, alpha 2M and transferrin are positive acute phase proteins in this species. While both interleukin-1 and tumour necrosis factor regulate biosynthesis of a number of these acute phase proteins in rabbit primary hepatocyte cultures, neither of these monokines induced C-reactive protein synthesis. Comparison of these findings with those in human hepatoma cell lines, in which interleukin-1 does not induce serum amyloid A synthesis, suggests that the effect of interleukin-1 on serum amyloid A synthesis may be indirect.

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Differential Cytokine-Induced Responses of Polarized Microglia

Brain Sciences ◽

10.3390/brainsci11111482 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1482

Author(s):

Priyanka Chauhan ◽

Wen S. Sheng ◽

Shuxian Hu ◽

Sujata Prasad ◽

James R. Lokensgard

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Cell Polarization ◽

Microglial Cells ◽

Color Flow ◽

Arginase 1 ◽

Activated State ◽

Ifn Γ ◽

Anti Inflammatory ◽

Differential Responses

The role of select pro- and anti-inflammatory mediators in driving microglial cell polarization into classically (M1), or alternatively, (M2) activated states, as well as the subsequent differential responses of these induced phenotypes, was examined. Expression of PD-L1, MHC-II, MHC-I, arginase 1 (Arg-1), and inducible nitric oxide synthase (iNOS) was assessed using multi-color flow cytometry. We observed that both pro- and anti-inflammatory mediators induced PD-L1 expression on non-polarized microglia. Moreover, IFN-γ stimulated significant MHC class I and II expression on these cells. Interestingly, we observed that only IL-4 treatment induced Arg-1 expression, indicating M2 polarization. These M2 cells were refractory to subsequent depolarization and maintained their alternatively activated state. Furthermore, PD-L1 expression was significantly induced on these M2-polarized microglia after treatment with pro-inflammatory mediators, but not anti-inflammatory cytokines. In addition, we observed that only LPS induced iNOS expression in microglial cells, indicating M1 polarization. Furthermore, IFN-γ significantly increased the percentage of M1-polarized microglia expressing iNOS. Surprisingly, when these M1-polarized microglia were treated with either IL-6 or other anti-inflammatory cytokines, they returned to their non-polarized state, as demonstrated by significantly reduced expression of iNOS. Taken together, these results demonstrate differential responses of microglial cells to mediators present in dissimilar microenvironments.

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Modulation of interleukin-1 and tumor necrosis factor expression by ?-adrenergic agonists in mouse ameboid microglial cells

Experimental Brain Research ◽

10.1007/bf00228965 ◽

1991 ◽

Vol 86 (2) ◽

Cited By ~ 88

Author(s):

E. Hetier ◽

J. Ayala1 ◽

A. Bousseau ◽

A. Prochiantz1

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Microglial Cells ◽

Adrenergic Agonists ◽

Factor Expression ◽

Tumor Necrosis Factor Expression ◽

Necrosis Factor

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Triptolide Inhibits Preformed Fibril-Induced Microglial Activation by Targeting the MicroRNA155-5p/SHIP1 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6527638 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 6

Author(s):

Yang Feng ◽

Chuyun Zheng ◽

Yajun Zhang ◽

Changyang Xing ◽

Wenbin Cai ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Microglial Activation ◽

Chinese Herb ◽

Enzyme Linked Immunosorbent Assay ◽

Protective Effects ◽

Toll Like Receptor ◽

Downstream Target ◽

Traditional Chinese Herb ◽

Inflammatory Component ◽

Human Wild Type

Evidence suggests that various forms of α-synuclein- (αSyn-) mediated microglial activation are associated with the progression of Parkinson’s disease. MicroRNA-155-5p (miR155-5p) is one of the most important microRNAs and enables a robust inflammatory response. Triptolide (T10) is a natural anti-inflammatory component, isolated from a traditional Chinese herb. The objective of the current study was to identify the role and potential regulatory mechanism of T10 in αSyn-induced microglial activation via the miR155-5p mediated SHIP1 signaling pathway. Mouse primary microglia were exposed to monomers, oligomers, and preformed fibrils (PFFs) of human wild-type αSyn, respectively. The expressions of TNFα and IL-1β, measured by enzyme-linked immunosorbent assay (ELISA) and qPCR, demonstrated that PFFs initiated the strongest immunogenicity in microglia. Application of inhibitors of toll-like receptor (TLR) 1/2, TLR4, and TLR9 indicated that PFFs activated microglia mainly via the NF-κB pathway by binding TLR1/2 and TLR4. Treatment with T10 significantly suppressed PFF-induced microglial activation and attenuated the release of proinflammatory cytokines including TNFα and IL-1β. Levels of IRAK1, TRAF6, IKKα/β, p-IKKα/β, NF-κB, p-NF-κB, PI3K, p-PI3K, t-Akt, p-Akt and SHIP1 were measured via Western blot. Levels of miR155-5p were measured by qPCR. The results demonstrated that SHIP1 acted as a downstream target molecule of miR155-5p. Treatment with T10 did not alter the expression of IRAK1 and TRAF6, but significantly decreased the expression of miR155-5p, resulting in upregulation of SHIP1 and repression of NF-κB activity, suggesting inhibition of inflammation and microglial activation. The protective effects of T10 were abolished by the use of SHIP1 siRNA and its inhibitor, 3AC, and miR155-5p mimics. In conclusion, our results demonstrated that treatment with T10 suppressed microglial activation and attenuated the release of proinflammatory cytokines by suppressing NF-κB activity via targeting the miR155-5p/SHIP1 pathway in PFFs-induced microglial activation.

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