Pain is a signal of inflammation that can have both protective and pathogenic effects.Macrophages,significant components of the immune system,play crucial roles in the occurrence and development of pain,particularly i...Pain is a signal of inflammation that can have both protective and pathogenic effects.Macrophages,significant components of the immune system,play crucial roles in the occurrence and development of pain,particularly in neuroimmune communication.Macrophages exhibit plasticity and heterogeneity,adopting either pro-inflammatory M1 or anti-inflammatory M2 phenotypes depending on their functional orientation.Recent research highlights the contribution of macrophages to pain dynamics by undergoing changes in their functional polarity,leading to macrophage activation,tissue infiltration,and cytokine secretion.M1 macrophages release pro-inflammatory mediators that are not only essential in defending against infections,but also contributing to tissue damage and the elicitation of pain.However,this process can be counteracted by M2 macrophages,facilitating pain relief through producing anti-inflammatory cytokines and opioid peptides or enhancing efferocytosis.M1 and M2 macrophages play important roles in both the initiation and mitigation of pain.展开更多
Background&Objective Tumor-associated macrophages(TAM)are induced by many cytokines,such as IL-4,IL-10,IL-13,and are considered to be of the M2 phenotype,which provides an immunosuppressive microenvironment for tu...Background&Objective Tumor-associated macrophages(TAM)are induced by many cytokines,such as IL-4,IL-10,IL-13,and are considered to be of the M2 phenotype,which provides an immunosuppressive microenvironment for tumor growth.However,biomechanistssuggest that cells in the tumor microenvironment are affected not only by chemical signals but also mechanical factors,of which the stiffness of tissues is a major determinant.Compared with normal tissues,including the peri-tumor tissues,tumor tissues are more rigid.Heretofore,the influence,on the differentiation and function of macrophages,of the differences in such physical aspect between展开更多
Since the beginning of gene therapy, most of genetransfection were focused on the tumor cells or effectorcells. We selected macrophages as the target cells of genetransfection because they are not only antitumor effec...Since the beginning of gene therapy, most of genetransfection were focused on the tumor cells or effectorcells. We selected macrophages as the target cells of genetransfection because they are not only antitumor effectorcells but also antigen-presenting cells.They act as abridge connecting tumor cells with immune effector cells.Two cytokines we chosen are closely linkcd with thefunctions of macrophage. IFN-γis a principle factor toactivate macrophages and it incrcases MHC expression ofthem which can improve their antigen presenting ability.M-CSF is an important cytokine to keep theproliferation, differentiation and maturation ofmacrophage progenitor cells. In this study, we used展开更多
Induction of tumor-specific cellular immune responseis very important in the cancer therapy. In this study,we used tumor antigen obtained by thaw of melanomacells to pulse M-CSF or/and IFN-γ gene-modificdmacrophages ...Induction of tumor-specific cellular immune responseis very important in the cancer therapy. In this study,we used tumor antigen obtained by thaw of melanomacells to pulse M-CSF or/and IFN-γ gene-modificdmacrophages before in viro infusion. Tumor membraneantigens could be phagocytosed by macrophages inculture. Antigen processing and mcxlulation of thepresentation can be achieved before macrophageinjection. The tumor antigens will be processedintracellularly by macrophages and thereafter展开更多
MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses. In this study, we found that activation of toll-like receptor 4 （TLR4） rapidly increased the level of microRNA-124 （miR- ...MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses. In this study, we found that activation of toll-like receptor 4 （TLR4） rapidly increased the level of microRNA-124 （miR- 124） in lipopolysaccharide （LPS）-treated macrophages and mice. MiR-124 knockdown significantly increased the production of the pro-inflammatory cytokine TNF-oL at the post-transcriptional level in LPS-triggered macrophages. Furthermore, miR-124 knockdown or overexpression significanly increased or decreased the protein stability of TNF- α. We found miR-124 directly targeted ubiquitin-specific proteases 2 （USP2） and 14 （USP14）, two components of deubiquitinating enzymes. Knockdown of USP2 and USP14 attenuated the miR-124-mediated protein degradation of TNF-α. Together, our data identify miR-124 as an important feedback negative regulator for LPS-induced pro- duction of TNF-α by targeting USP2 and USP14, thus outlining new mechanisms for fine-tuning the TLR-triggered inflammatory response.展开更多
Aim Accumulated evidence suggests that M2-1ike polarized tumor associated macrophages （TAMs） plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-1ike TAMs as an appealing t...Aim Accumulated evidence suggests that M2-1ike polarized tumor associated macrophages （TAMs） plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-1ike TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2- like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-1ike macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKαl activation in macrophage and silencing of AMPKotl partially abrogated the inhibitory effect of metformin in IL-13 induced M2-1ike polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-1ike polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-1ike macrophage was decreased and the anti-metastatic effect of metformin was abolished the area of pericyte-coated vessels was increased. Further, when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-1ike polarization of macrophages partially through AMPKαl, which plays an im- portant role in metformin inhibited metastasis of Lewis lung cancer.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease,which is characterized by synovial inflammation.Hyperplasia sublining macrophages found in synovium is an early hallmark of RA and effective treatment results in their ...Rheumatoid arthritis(RA)is an autoimmune disease,which is characterized by synovial inflammation.Hyperplasia sublining macrophages found in synovium is an early hallmark of RA and effective treatment results in their diminution.However,the origin of these sublining macrophages in synovium(including infiltrated macrophages and tissue-resident macrophages)are still unknown both in animal models of arthritis and RA patients,let alone the differences and feature of these macrophages.In rheumatic synovium,macrophages are submitted to a large variety of micro-environmental signals which influence the phenotypic polarization and activation of macrophages.Understanding the mechanisms and functional consequences of the heterogeneous macrophages will contribute to confirm their potential role in synovial inflammation development.Furthermore,research on macrophage plasticity to soft-control their phenotypic polarization could lead to novel therapeutic approaches.展开更多
Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.E...Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.Emerging evidence suggests that macrophage-mediated immune responses are efficiently regulated by the ubiquitination modification,which is responsible for normal immune responses.However,numerous studies indicates that the aberrant activation or inhibition of macrophage-mediated immune responses occurs in inflammation,mainly caused by dysregulated ubiquitination modification due to E3 ubiquitin ligases mutations or abnormal expression.Notably,E3 ubiquitin ligases,responsible for recognizing the substrates,are key enzymes in the ubiquitin proteasome system(UPS)composed of ubiquitin(Ub),ubiquitin-activating E1 enzymes,ubiquitin-conjugating E2 enzymes,E3 ubiquitin ligases,26S proteasome,and deubiquitinating enzymes.Intriguingly,several E3 ubiquitin ligases are involved in the regulation of some common signal pathways in macrophage-mediated inflammation,including Toll-like receptors(TLRs),nucleotide-binding oligomerization domain(NOD)-like receptors(NLRs),RIG-I-like receptors(RLRs),C-type lectin receptors(CLRs)and the receptor for advanced glycation end products(RAGE).Herein,we summarized the physiological and pathological roles of E3 ligases in macrophage-mediated inflammation,as well as the inhibitors and agonists targeting E3 ligases in macrophage mediated inflammation,providing the new ideas for targeted therapies in macrophage-mediated inflammation caused aberrant function of E3 ligases.展开更多
The vagus nerve can control inflammatory response through a ＇ cholinergic anti-inflammatory pathway＇, which is mediated by the α7-nicotinic acetylcholine receptor （α7nAChR） on macrophages. However, the intracel-...The vagus nerve can control inflammatory response through a ＇ cholinergic anti-inflammatory pathway＇, which is mediated by the α7-nicotinic acetylcholine receptor （α7nAChR） on macrophages. However, the intracel- lular mechanisms that link α7nAChR activation and pro-inflammatory cytokine production remain not well under- stood. In this study, we found that miR-124 is upregulated by cholinergic agonists in LPS-exposed cells and mice. Utilizing miR-124 mimic and siRNA knockdown, we demonstrated that miR-124 is a critical mediator for the cho- linergic anti-inflammatory action. Furthermore, our data indicated that miR-124 modulates LPS-induced cytokine production by targeting signal transducer and activator of transcription 3 （STAT3） to decrease IL-6 production and TNF-α converting enzyme （TACE） to reduce TNF-ot release. These results also indicate that miR-124 is a potential therapeutic target for the treatment of inflammatory diseases.展开更多
Macrophage inflammatory protein-l, a recentlycharacterized chemokine, consists of two chains (αand β). MIP-lα has been shown to exert strongchemotactic effect on neutrophils, monocytes and Tlymphocytes. In the pres...Macrophage inflammatory protein-l, a recentlycharacterized chemokine, consists of two chains (αand β). MIP-lα has been shown to exert strongchemotactic effect on neutrophils, monocytes and Tlymphocytes. In the present study, the B16 melanomacells were transfected with recombinant adenoviruscontaining MIP-lα gene. The biological characteri-zation of the MIP-1α gene transfected B16 melanomacells was investigated. The level of MIP-1α in thesupernatant of gene-transfected melanoma cells was368±24 ng/ml/10~6/24hr.. By using Boyden chambersystem, this supernatant showed strong chemotacticactivity for NK cells, CD4^+ T cells, CD8^+ T cells orthe freshly isolated peritoneal macrophages in vitro.Though the in vitro growth of the gene-transfected B16 melanoma cclls was not aftered, the in vivogrowth of the tumor cells subcutaneously inoculatedwas significantly inhibited. The infiltration ofinflammatory cells into the tumor mass formed bygene-transfected B16 cells was much more obviousthan that by展开更多
It has been demonstrated that tbe critical role ofbone marrow stromal cells (HMSCs ) is to sustain theselfrenewal of pluripotent hematopoietic stem cells andmaintain the homeostasis of bone marrow hematopoiesismicroen...It has been demonstrated that tbe critical role ofbone marrow stromal cells (HMSCs ) is to sustain theselfrenewal of pluripotent hematopoietic stem cells andmaintain the homeostasis of bone marrow hematopoiesismicroenvironment. BMSC progenitor can differentiateinto several clements including macrophages, endothelialcells, fibroblasts and some other cells. Almost展开更多
Several features of adenoviruses make them anattractive option as a vehicle to transfer genes intoprimary malignant neoplasms in vivo. These viruseshave low pathogenicity in humans and are notneurotoxic. In addition, ...Several features of adenoviruses make them anattractive option as a vehicle to transfer genes intoprimary malignant neoplasms in vivo. These viruseshave low pathogenicity in humans and are notneurotoxic. In addition, high titers of the virus can beachieved to allow higher levels of gene transfectionefficiency than the other vector systems. In vivotumorigenicity of G422 glioblastoma cells transfectedwith IL-2 and/or IL-3 genes decreased significantly inour privious report. In this study, recombinantadenoviruses were used to evaluate the therapeuticpotential of combined IL-2/IL-3 gene therapy in thetreatment of established subcutaneous tumor model ofG422 glioblastoma. Murine IL-2, IL-3 recombinantadenoviruses (2×10~8 pfu) were injected directly展开更多
Numerous animal experiments and clinical trialshave demonstrated that the effects of systemicantitumor immune responses are closely correlatedwith the infiltration of effector cells, e. g.macrophages, T cells and NK c...Numerous animal experiments and clinical trialshave demonstrated that the effects of systemicantitumor immune responses are closely correlatedwith the infiltration of effector cells, e. g.macrophages, T cells and NK cells, at the site oftumor. In previous studies, we have established theIL-2, IL-4, IL-6 gene-transfected B16F10展开更多
OBJECTIVE To investigate the isolation,extraction,purification,and immunomodulatory activities in vitro and in vivo of polysaccharides from four different species of Dendrobiumherbs widely used in Singapore.METHODS To...OBJECTIVE To investigate the isolation,extraction,purification,and immunomodulatory activities in vitro and in vivo of polysaccharides from four different species of Dendrobiumherbs widely used in Singapore.METHODS To apply the classic method of water extraction and ethanol precipitation and the gel column chromatography technique,the polysaccharides from four species of Dendrobium herbs(D.moniliforme,D.crystallinum,D.primulinum,D.chrysanthum)were obtained.The polysaccharides were tested first on RAW 264.7 cell line with MTT method to test the effect of polysaccharides on macrophages.The two polysaccharides from D.moniliforme were found to promote proliferation of the cells,and were then tested on mice splenocyte primary cell culture.The same polysaccharides were also injected to female BALB/c mice at various doses for 21 dto see whether they would have affected the organs,especially the livers,spleens and thymuses.RESULTS Out of the 4 Dendrobiumspecies tested,it was found that polysaccharides from D.moniliformeto be most supportive of the proliferation of macrophages in a dose-dependent manner,with increasing effect with the increasing doses used.Polysaccharides from D.chrysanthumand D.crystallinum were also found to act similarly albeit to a lesser extent.The two D.moniliforme polysaccharides were also found to greatly enhance the proliferation of mouse splenocytes in vitro and growth of the spleen in vivo.CONCLUSION The immunomodulatory activities in vitro and in vivo of polysaccharides from four species of Dendrobium herbs were different.Their diverse chemical characters might contribute to their varied bioactivity,which should be further investigated.In addition,it was suggested that the polysaccharides from D.moniliforme could be potential immunostimulants used in the healthcare and food industry.展开更多
OBJECTIVE Interleukin(IL)-1β,one of the principal inflammatory cytokines mainly secreted by monocytes and macrophages,is produced by cleavage of the inactive pro-IL^(-1)βprecursor by caspase-1 via the NLRP3 inflamma...OBJECTIVE Interleukin(IL)-1β,one of the principal inflammatory cytokines mainly secreted by monocytes and macrophages,is produced by cleavage of the inactive pro-IL^(-1)βprecursor by caspase-1 via the NLRP3 inflammasome complex.The fruits of Garcinia cambogia(Clusiaceae)are widely developed as health products for anti-obese purpose.14-deoxygarcinol(DOG)is a polyisoprenylated benzophenone from the fruits of G.cambogia,which showed potent anti-inflammatory effect in our previous study.The objective of this study was to explore the anti-inflammatory mechanism of DOG and its roles in alleviating adipose tissue inflammation and insulin resistance.METHODS The anti-inflammatory effect of DOG was evaluated on LPS plus nigericin-induced THP-1 macrophages.The expression of NLRP3 inflammasome complex proteins was analyzed by Western blotting,immunofluorescence staining and co-immunoprecipitation.The pro-inflammatory cytokines levels were determined by ELISA kits.RESULTS DOG increased the expression of Sirtuin 2(SIRT2)deacetylase and enhanced its deacetylating activity to suppress the NLRP3 inflammasome activation and IL^(-1)βsecretion in THP-1 macrophages.Moreover,DOG attenuated macrophage conditioned medium-induced inflammatory responses in adipocytes and blocked THP-1 macrophages migration towards 3T3-L1 adipocytes.CONCLUSION DOG attenuated the inflammatory crosstalk between macrophages and adipocytes through SIRT2-mediated NLRP3 inflammasome inhibition,which might be used for the treatment of adipose tissue inflammation-related metabolic disorders.展开更多
OBJECTIVE In order to investigate the possible anti-tumor molecular mechanisms of gecko polypeptide mixture(GPM).METHODS RNA-seq technology was used to identify the differentially expressed genes of human hepatocellul...OBJECTIVE In order to investigate the possible anti-tumor molecular mechanisms of gecko polypeptide mixture(GPM).METHODS RNA-seq technology was used to identify the differentially expressed genes of human hepatocellular carcinoma(HCC)HepG2 cells treated with or without GPM.The HepG2 cells were treated with different concentration of GPM(0,0.1,0.2,0.3,0.4 mg·mL^(-1))for 6 h,12 h and 24 h,respectively.MTT assay was used to detect the viability of HepG2 cells.DAPI fluorescence staining was performed to observe nucleus morphological changes of HepG2 cells.Western blot analysis was applied to observe the expression of apoptosis-related proteins in HepG2 cells.RESULTS The results showed that GPM could induce HepG2 cells apoptosis and influence HepG2 cells proliferation in a dose-dependent manner.We applied many analysis methods,including differentially expressed genes analysis,Gene Ontology(GO)enrichment analysis,KEGG pathway enrichment analysis,protein-protein interaction network analysis to screen out possible molecular mechanisms.ER-nucleus signaling pathway,cellular response to stress and apoptotic processes were identified the potential anti-cancer molecular biological process of GPM.GPM may also induce apoptosis in HepG2 cells via endoplasmic reticulum stress pathway.The mechanism is closely related to ERs,which might be beneficial for clinical therapy of HCC.CONCLUSION GPM can inhibit cells proliferation and induce apoptosis in HepG2 cells.The gene expression profile of GPM in HepG2 cells was obtained.The present study revealed the potential anti-tumor mechanism of GPM.展开更多
A wide variety of human tumors express interleukin10 (IL-10) for reasons poorly understood. We haveanalysed the effect of spontaneous IL-10 expression by amouse tumor (J558L) on its immunparalysing effect.Because cros...A wide variety of human tumors express interleukin10 (IL-10) for reasons poorly understood. We haveanalysed the effect of spontaneous IL-10 expression by amouse tumor (J558L) on its immunparalysing effect.Because cross-priming" of T cells by host antigenpresenting cells for MHC class I restricted tumor antigensis a major pathway for induction of tumor immunity andthat is enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), we expressed this cytokinein J558L cells. GM-CSF secreting cells were not展开更多
OBJECTIVE Oleoylethanolamide(OEA) has shown neuroprotective effect in treating acute and chronic ischemic stroke.However,it is unclear whether OEA is able to modulate microglia/macrophage polarization,which has recent...OBJECTIVE Oleoylethanolamide(OEA) has shown neuroprotective effect in treating acute and chronic ischemic stroke.However,it is unclear whether OEA is able to modulate microglia/macrophage polarization,which has recently been documented to be important in the pathology of ischemic stroke.This study explored the potential role of OEA in modulating the microglial phenotypes.METHODS In vivo,middle cerebral artery occlusion(MCAO) was induced in both PPARα-/-(KO) and wild-type(WT)mice.In vitro,primary cortical microglia or neuron or coculture from KO/WT mice was subjected to oxygen glucose deprivation(OGD).Western blotting and immunofluorescence were used for detecting the specialized protein expression of M1/M2,such as CD206 and CD16/32.q PCR was utilized to detect the signature gene change of M1/M2.RESULTS OEA significantly reduced neuron damage of mice after MCAO.More importantly,OEA promoted microglia/macrophage transferring from inflammatory M1 phenotype to a protective,anti-inflammatory M2 phenotype in vivo or in vitro.Interestingly,these benifical effects of OEA could not be observed in the KO mice or KO microglia.CONCLUSION Our results reveal a novel pharmacological effect of OEA in modulating microglia/macrophage polarization after MCAO,thus depening our understanding of neuroprotective mechanisms of OEA in treatment of ischemic stroke.Furthermore,this new mechanism may allow OEA to be used in many other microglia/macrophage polarizationrelated inflammatory diseases.展开更多
Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of ...Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of α3- nAChR in the inflammatory responses of atherosclerosis. Methods The inflammatory indicators were detected in mouse macrophage, adipocytes and mouse aortic endothelial cells （MAECs） after the α3-nAChR was antagonized or after the α3-nAChR gene was silenced. Meanwhile, atherogenesis was induced in the apolipoprotein E knock-out （ ApoE^ -/- ） mice after fed with an atherogenic high-fat diet for 7 weeks. Results In MAECs, the lipopolysaccha- ride （LPS）-stimulated secretions of the adhesion molecules and inflammatory cytokines were significantly enhanced （30%± 80% ） after pretreatment with α-Conotoxin MII （an antagonist for α3-nAChR） or after knock-down with α3-nAChR gene. In adipocytes, the knock-down of α3 gene promoted the generations of the proin？ ammatory adi- pokines or cytokines but decreased the production of adiponectin, an anti-inflammatory adipokine, by 29.29 ± 9.43%. In macrophage silenced with α3-nAChR gene, the M1 （classical） activation was predominantly stimula- ted, whereas the M2 （alternative） activation was suppressed. In addition, the amount of the atherosclerotic lesions and the infiltration of the M1 type activated macrophages into the arterial wall were markedly elevated in the α- Conotoxin MII-treated ApoE -/- mice. Conclusion The α3-nAChR may play a pivotal role in regulating the atherogenesis through influencing the inflammatory responses of ECs, macrophages and adipocytes. The mecha- nisms involve the regulations of multiple cell signaling pathways.展开更多
基金supported by the Natural Science Foundation of Hunan Province(2021JJ41060,2022JJ30972)the Changsha Municipal Natural Science Foundation(kq2014280)+1 种基金the Research Program Project of Hunan Health Commission(B202304119634)China。
文摘Pain is a signal of inflammation that can have both protective and pathogenic effects.Macrophages,significant components of the immune system,play crucial roles in the occurrence and development of pain,particularly in neuroimmune communication.Macrophages exhibit plasticity and heterogeneity,adopting either pro-inflammatory M1 or anti-inflammatory M2 phenotypes depending on their functional orientation.Recent research highlights the contribution of macrophages to pain dynamics by undergoing changes in their functional polarity,leading to macrophage activation,tissue infiltration,and cytokine secretion.M1 macrophages release pro-inflammatory mediators that are not only essential in defending against infections,but also contributing to tissue damage and the elicitation of pain.However,this process can be counteracted by M2 macrophages,facilitating pain relief through producing anti-inflammatory cytokines and opioid peptides or enhancing efferocytosis.M1 and M2 macrophages play important roles in both the initiation and mitigation of pain.
文摘Background&Objective Tumor-associated macrophages(TAM)are induced by many cytokines,such as IL-4,IL-10,IL-13,and are considered to be of the M2 phenotype,which provides an immunosuppressive microenvironment for tumor growth.However,biomechanistssuggest that cells in the tumor microenvironment are affected not only by chemical signals but also mechanical factors,of which the stiffness of tissues is a major determinant.Compared with normal tissues,including the peri-tumor tissues,tumor tissues are more rigid.Heretofore,the influence,on the differentiation and function of macrophages,of the differences in such physical aspect between
文摘Since the beginning of gene therapy, most of genetransfection were focused on the tumor cells or effectorcells. We selected macrophages as the target cells of genetransfection because they are not only antitumor effectorcells but also antigen-presenting cells.They act as abridge connecting tumor cells with immune effector cells.Two cytokines we chosen are closely linkcd with thefunctions of macrophage. IFN-γis a principle factor toactivate macrophages and it incrcases MHC expression ofthem which can improve their antigen presenting ability.M-CSF is an important cytokine to keep theproliferation, differentiation and maturation ofmacrophage progenitor cells. In this study, we used
文摘The moditication of tumor cells or effcor cellsusing cytokine genes as a strategy to enhance hostantitumor immunity has been studied intensively over
文摘Induction of tumor-specific cellular immune responseis very important in the cancer therapy. In this study,we used tumor antigen obtained by thaw of melanomacells to pulse M-CSF or/and IFN-γ gene-modificdmacrophages before in viro infusion. Tumor membraneantigens could be phagocytosed by macrophages inculture. Antigen processing and mcxlulation of thepresentation can be achieved before macrophageinjection. The tumor antigens will be processedintracellularly by macrophages and thereafter
文摘MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses. In this study, we found that activation of toll-like receptor 4 （TLR4） rapidly increased the level of microRNA-124 （miR- 124） in lipopolysaccharide （LPS）-treated macrophages and mice. MiR-124 knockdown significantly increased the production of the pro-inflammatory cytokine TNF-oL at the post-transcriptional level in LPS-triggered macrophages. Furthermore, miR-124 knockdown or overexpression significanly increased or decreased the protein stability of TNF- α. We found miR-124 directly targeted ubiquitin-specific proteases 2 （USP2） and 14 （USP14）, two components of deubiquitinating enzymes. Knockdown of USP2 and USP14 attenuated the miR-124-mediated protein degradation of TNF-α. Together, our data identify miR-124 as an important feedback negative regulator for LPS-induced pro- duction of TNF-α by targeting USP2 and USP14, thus outlining new mechanisms for fine-tuning the TLR-triggered inflammatory response.
文摘Aim Accumulated evidence suggests that M2-1ike polarized tumor associated macrophages （TAMs） plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-1ike TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2- like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-1ike macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKαl activation in macrophage and silencing of AMPKotl partially abrogated the inhibitory effect of metformin in IL-13 induced M2-1ike polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-1ike polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-1ike macrophage was decreased and the anti-metastatic effect of metformin was abolished the area of pericyte-coated vessels was increased. Further, when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-1ike polarization of macrophages partially through AMPKαl, which plays an im- portant role in metformin inhibited metastasis of Lewis lung cancer.
基金supported by National Natural Science Foundation of China(31200675,81573443,81330081 and 81673444)Specialized Research Fund for the Doctoral Program of Higher Education(20123420110003)Scientific Research of BSKY from Anhui Medical University(XJ201215)
文摘Rheumatoid arthritis(RA)is an autoimmune disease,which is characterized by synovial inflammation.Hyperplasia sublining macrophages found in synovium is an early hallmark of RA and effective treatment results in their diminution.However,the origin of these sublining macrophages in synovium(including infiltrated macrophages and tissue-resident macrophages)are still unknown both in animal models of arthritis and RA patients,let alone the differences and feature of these macrophages.In rheumatic synovium,macrophages are submitted to a large variety of micro-environmental signals which influence the phenotypic polarization and activation of macrophages.Understanding the mechanisms and functional consequences of the heterogeneous macrophages will contribute to confirm their potential role in synovial inflammation development.Furthermore,research on macrophage plasticity to soft-control their phenotypic polarization could lead to novel therapeutic approaches.
文摘Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.Emerging evidence suggests that macrophage-mediated immune responses are efficiently regulated by the ubiquitination modification,which is responsible for normal immune responses.However,numerous studies indicates that the aberrant activation or inhibition of macrophage-mediated immune responses occurs in inflammation,mainly caused by dysregulated ubiquitination modification due to E3 ubiquitin ligases mutations or abnormal expression.Notably,E3 ubiquitin ligases,responsible for recognizing the substrates,are key enzymes in the ubiquitin proteasome system(UPS)composed of ubiquitin(Ub),ubiquitin-activating E1 enzymes,ubiquitin-conjugating E2 enzymes,E3 ubiquitin ligases,26S proteasome,and deubiquitinating enzymes.Intriguingly,several E3 ubiquitin ligases are involved in the regulation of some common signal pathways in macrophage-mediated inflammation,including Toll-like receptors(TLRs),nucleotide-binding oligomerization domain(NOD)-like receptors(NLRs),RIG-I-like receptors(RLRs),C-type lectin receptors(CLRs)and the receptor for advanced glycation end products(RAGE).Herein,we summarized the physiological and pathological roles of E3 ligases in macrophage-mediated inflammation,as well as the inhibitors and agonists targeting E3 ligases in macrophage mediated inflammation,providing the new ideas for targeted therapies in macrophage-mediated inflammation caused aberrant function of E3 ligases.
文摘The vagus nerve can control inflammatory response through a ＇ cholinergic anti-inflammatory pathway＇, which is mediated by the α7-nicotinic acetylcholine receptor （α7nAChR） on macrophages. However, the intracel- lular mechanisms that link α7nAChR activation and pro-inflammatory cytokine production remain not well under- stood. In this study, we found that miR-124 is upregulated by cholinergic agonists in LPS-exposed cells and mice. Utilizing miR-124 mimic and siRNA knockdown, we demonstrated that miR-124 is a critical mediator for the cho- linergic anti-inflammatory action. Furthermore, our data indicated that miR-124 modulates LPS-induced cytokine production by targeting signal transducer and activator of transcription 3 （STAT3） to decrease IL-6 production and TNF-α converting enzyme （TACE） to reduce TNF-ot release. These results also indicate that miR-124 is a potential therapeutic target for the treatment of inflammatory diseases.
文摘Macrophage inflammatory protein-l, a recentlycharacterized chemokine, consists of two chains (αand β). MIP-lα has been shown to exert strongchemotactic effect on neutrophils, monocytes and Tlymphocytes. In the present study, the B16 melanomacells were transfected with recombinant adenoviruscontaining MIP-lα gene. The biological characteri-zation of the MIP-1α gene transfected B16 melanomacells was investigated. The level of MIP-1α in thesupernatant of gene-transfected melanoma cells was368±24 ng/ml/10~6/24hr.. By using Boyden chambersystem, this supernatant showed strong chemotacticactivity for NK cells, CD4^+ T cells, CD8^+ T cells orthe freshly isolated peritoneal macrophages in vitro.Though the in vitro growth of the gene-transfected B16 melanoma cclls was not aftered, the in vivogrowth of the tumor cells subcutaneously inoculatedwas significantly inhibited. The infiltration ofinflammatory cells into the tumor mass formed bygene-transfected B16 cells was much more obviousthan that by
文摘It has been demonstrated that tbe critical role ofbone marrow stromal cells (HMSCs ) is to sustain theselfrenewal of pluripotent hematopoietic stem cells andmaintain the homeostasis of bone marrow hematopoiesismicroenvironment. BMSC progenitor can differentiateinto several clements including macrophages, endothelialcells, fibroblasts and some other cells. Almost
文摘Several features of adenoviruses make them anattractive option as a vehicle to transfer genes intoprimary malignant neoplasms in vivo. These viruseshave low pathogenicity in humans and are notneurotoxic. In addition, high titers of the virus can beachieved to allow higher levels of gene transfectionefficiency than the other vector systems. In vivotumorigenicity of G422 glioblastoma cells transfectedwith IL-2 and/or IL-3 genes decreased significantly inour privious report. In this study, recombinantadenoviruses were used to evaluate the therapeuticpotential of combined IL-2/IL-3 gene therapy in thetreatment of established subcutaneous tumor model ofG422 glioblastoma. Murine IL-2, IL-3 recombinantadenoviruses (2×10~8 pfu) were injected directly
文摘Numerous animal experiments and clinical trialshave demonstrated that the effects of systemicantitumor immune responses are closely correlatedwith the infiltration of effector cells, e. g.macrophages, T cells and NK cells, at the site oftumor. In previous studies, we have established theIL-2, IL-4, IL-6 gene-transfected B16F10
基金The project supported by The Ministry of Education Translational R&D and Innovation Fund(MOE2012-TIF-1-G-065),Singapore
文摘OBJECTIVE To investigate the isolation,extraction,purification,and immunomodulatory activities in vitro and in vivo of polysaccharides from four different species of Dendrobiumherbs widely used in Singapore.METHODS To apply the classic method of water extraction and ethanol precipitation and the gel column chromatography technique,the polysaccharides from four species of Dendrobium herbs(D.moniliforme,D.crystallinum,D.primulinum,D.chrysanthum)were obtained.The polysaccharides were tested first on RAW 264.7 cell line with MTT method to test the effect of polysaccharides on macrophages.The two polysaccharides from D.moniliforme were found to promote proliferation of the cells,and were then tested on mice splenocyte primary cell culture.The same polysaccharides were also injected to female BALB/c mice at various doses for 21 dto see whether they would have affected the organs,especially the livers,spleens and thymuses.RESULTS Out of the 4 Dendrobiumspecies tested,it was found that polysaccharides from D.moniliformeto be most supportive of the proliferation of macrophages in a dose-dependent manner,with increasing effect with the increasing doses used.Polysaccharides from D.chrysanthumand D.crystallinum were also found to act similarly albeit to a lesser extent.The two D.moniliforme polysaccharides were also found to greatly enhance the proliferation of mouse splenocytes in vitro and growth of the spleen in vivo.CONCLUSION The immunomodulatory activities in vitro and in vivo of polysaccharides from four species of Dendrobium herbs were different.Their diverse chemical characters might contribute to their varied bioactivity,which should be further investigated.In addition,it was suggested that the polysaccharides from D.moniliforme could be potential immunostimulants used in the healthcare and food industry.
基金National Natural Science Foundation of China(81872754)Research Fund of University of Macao(MYRG2018-00037-ICMS)and Science and Technology Development Fund,Macao SAR(FDCT 0031/2019/A1)。
文摘OBJECTIVE Interleukin(IL)-1β,one of the principal inflammatory cytokines mainly secreted by monocytes and macrophages,is produced by cleavage of the inactive pro-IL^(-1)βprecursor by caspase-1 via the NLRP3 inflammasome complex.The fruits of Garcinia cambogia(Clusiaceae)are widely developed as health products for anti-obese purpose.14-deoxygarcinol(DOG)is a polyisoprenylated benzophenone from the fruits of G.cambogia,which showed potent anti-inflammatory effect in our previous study.The objective of this study was to explore the anti-inflammatory mechanism of DOG and its roles in alleviating adipose tissue inflammation and insulin resistance.METHODS The anti-inflammatory effect of DOG was evaluated on LPS plus nigericin-induced THP-1 macrophages.The expression of NLRP3 inflammasome complex proteins was analyzed by Western blotting,immunofluorescence staining and co-immunoprecipitation.The pro-inflammatory cytokines levels were determined by ELISA kits.RESULTS DOG increased the expression of Sirtuin 2(SIRT2)deacetylase and enhanced its deacetylating activity to suppress the NLRP3 inflammasome activation and IL^(-1)βsecretion in THP-1 macrophages.Moreover,DOG attenuated macrophage conditioned medium-induced inflammatory responses in adipocytes and blocked THP-1 macrophages migration towards 3T3-L1 adipocytes.CONCLUSION DOG attenuated the inflammatory crosstalk between macrophages and adipocytes through SIRT2-mediated NLRP3 inflammasome inhibition,which might be used for the treatment of adipose tissue inflammation-related metabolic disorders.
基金supported by Science and Technology Key Research Fund of Henan Province(142102310031)
文摘OBJECTIVE In order to investigate the possible anti-tumor molecular mechanisms of gecko polypeptide mixture(GPM).METHODS RNA-seq technology was used to identify the differentially expressed genes of human hepatocellular carcinoma(HCC)HepG2 cells treated with or without GPM.The HepG2 cells were treated with different concentration of GPM(0,0.1,0.2,0.3,0.4 mg·mL^(-1))for 6 h,12 h and 24 h,respectively.MTT assay was used to detect the viability of HepG2 cells.DAPI fluorescence staining was performed to observe nucleus morphological changes of HepG2 cells.Western blot analysis was applied to observe the expression of apoptosis-related proteins in HepG2 cells.RESULTS The results showed that GPM could induce HepG2 cells apoptosis and influence HepG2 cells proliferation in a dose-dependent manner.We applied many analysis methods,including differentially expressed genes analysis,Gene Ontology(GO)enrichment analysis,KEGG pathway enrichment analysis,protein-protein interaction network analysis to screen out possible molecular mechanisms.ER-nucleus signaling pathway,cellular response to stress and apoptotic processes were identified the potential anti-cancer molecular biological process of GPM.GPM may also induce apoptosis in HepG2 cells via endoplasmic reticulum stress pathway.The mechanism is closely related to ERs,which might be beneficial for clinical therapy of HCC.CONCLUSION GPM can inhibit cells proliferation and induce apoptosis in HepG2 cells.The gene expression profile of GPM in HepG2 cells was obtained.The present study revealed the potential anti-tumor mechanism of GPM.
文摘A wide variety of human tumors express interleukin10 (IL-10) for reasons poorly understood. We haveanalysed the effect of spontaneous IL-10 expression by amouse tumor (J558L) on its immunparalysing effect.Because cross-priming" of T cells by host antigenpresenting cells for MHC class I restricted tumor antigensis a major pathway for induction of tumor immunity andthat is enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), we expressed this cytokinein J558L cells. GM-CSF secreting cells were not
基金Fundamental Research Funds for the Central Universities (20720180042)Health Science ResearchPersonnel Training Program of Fujian Province(2018-CXB-30)+2 种基金Natural Science Foundation of Fujian Province of China (2016J014152016D024)Science and Technology Pro
文摘OBJECTIVE Oleoylethanolamide(OEA) has shown neuroprotective effect in treating acute and chronic ischemic stroke.However,it is unclear whether OEA is able to modulate microglia/macrophage polarization,which has recently been documented to be important in the pathology of ischemic stroke.This study explored the potential role of OEA in modulating the microglial phenotypes.METHODS In vivo,middle cerebral artery occlusion(MCAO) was induced in both PPARα-/-(KO) and wild-type(WT)mice.In vitro,primary cortical microglia or neuron or coculture from KO/WT mice was subjected to oxygen glucose deprivation(OGD).Western blotting and immunofluorescence were used for detecting the specialized protein expression of M1/M2,such as CD206 and CD16/32.q PCR was utilized to detect the signature gene change of M1/M2.RESULTS OEA significantly reduced neuron damage of mice after MCAO.More importantly,OEA promoted microglia/macrophage transferring from inflammatory M1 phenotype to a protective,anti-inflammatory M2 phenotype in vivo or in vitro.Interestingly,these benifical effects of OEA could not be observed in the KO mice or KO microglia.CONCLUSION Our results reveal a novel pharmacological effect of OEA in modulating microglia/macrophage polarization after MCAO,thus depening our understanding of neuroprotective mechanisms of OEA in treatment of ischemic stroke.Furthermore,this new mechanism may allow OEA to be used in many other microglia/macrophage polarizationrelated inflammatory diseases.
文摘Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of α3- nAChR in the inflammatory responses of atherosclerosis. Methods The inflammatory indicators were detected in mouse macrophage, adipocytes and mouse aortic endothelial cells （MAECs） after the α3-nAChR was antagonized or after the α3-nAChR gene was silenced. Meanwhile, atherogenesis was induced in the apolipoprotein E knock-out （ ApoE^ -/- ） mice after fed with an atherogenic high-fat diet for 7 weeks. Results In MAECs, the lipopolysaccha- ride （LPS）-stimulated secretions of the adhesion molecules and inflammatory cytokines were significantly enhanced （30%± 80% ） after pretreatment with α-Conotoxin MII （an antagonist for α3-nAChR） or after knock-down with α3-nAChR gene. In adipocytes, the knock-down of α3 gene promoted the generations of the proin？ ammatory adi- pokines or cytokines but decreased the production of adiponectin, an anti-inflammatory adipokine, by 29.29 ± 9.43%. In macrophage silenced with α3-nAChR gene, the M1 （classical） activation was predominantly stimula- ted, whereas the M2 （alternative） activation was suppressed. In addition, the amount of the atherosclerotic lesions and the infiltration of the M1 type activated macrophages into the arterial wall were markedly elevated in the α- Conotoxin MII-treated ApoE -/- mice. Conclusion The α3-nAChR may play a pivotal role in regulating the atherogenesis through influencing the inflammatory responses of ECs, macrophages and adipocytes. The mecha- nisms involve the regulations of multiple cell signaling pathways.
