Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immuno...Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.展开更多
Inflammatory bowel disease(IBD)is a common and lifelong disabling gastrointestinal disease.Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response.Ade...Inflammatory bowel disease(IBD)is a common and lifelong disabling gastrointestinal disease.Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response.Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models.High extracellular adenosine suppresses and resolves chronic inflammation in IBD models.High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis.Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation. Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells,respectively. Increased extracellular adenosine levels activate the A2a receptor,which would reduce cytokines responsible for chronic inflammation.展开更多
Inflammatory bowel diseases(IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease.At the core of th...Inflammatory bowel diseases(IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease.At the core of these alterations are endothelial cells,whose continual adjustments in structure and function coordinate vascular supply,immune cell emigration,and regulation of the tissue environment.Expansion of the endothelium in IBD(angiogenesis),mediated by inflammatory growth factors,cytokines and chemokines,is a hallmark of active gut disease and is closely related to disease severity.The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines,growth factors,and adhesion molecules,altering coagulant capacity,barrier function and blood cell recruitment in injury.This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.展开更多
Toll-like receptors （TLRs） are probably the most important class of pattern-recognition receptors. Members of the TLR family play key roles in the both innate and adaptive immune responses. Recognition of pathogen-a...Toll-like receptors （TLRs） are probably the most important class of pattern-recognition receptors. Members of the TLR family play key roles in the both innate and adaptive immune responses. Recognition of pathogen-associated molecular patterns （PAMPs） by TLRs, either alone or in heterodimedzation with other TLR or non-TLR receptors, induces the production of signals that are responsible for the activation of genes important for an effective host defense, especially those of proinflammatory cytokines. Thus, TLRs are involved in the development of many pathological conditions including infectious diseases, tissue damage, and cancer especially. In this review, the contribution of TLRs to tumorgenesis is evaluated. We hope to provide new insight into the progression of cancer and more importantly into the potential for TLRs as targets of therapeutics.展开更多
Recent studies have shown that diet can affect the body＇s immunity. Roughage of dairy cows consists of a variety of plant materials which make different contributions to health. This study investigated the effect of ...Recent studies have shown that diet can affect the body＇s immunity. Roughage of dairy cows consists of a variety of plant materials which make different contributions to health. This study investigated the effect of different roughages on the immunity of dairy cows. Serum, peripheral blood mononuclear cells （PBMCs）, and milk samples were collected from 20 multiparous mid-lactation cows fed mixed forage （MF）- or corn straw （CS）-based diets. Ex- pression profile analysis was used to detect the differentially expressed genes （DEGs） from PBMCs. The results showed that milk protein in the MF group increased to 3.22 g/100 ml, while that of the CS group milk was 2.96 g/100 ml; by RNA sequencing, it was found that 1615 genes were differentially expressed between the CS group and the MF group among the 24027 analyzed probes. Gene ontology （GO） and pathway analysis of DEGs suggested that these genes （especially genes coding cytokines, chemokine and its receptors） are involved in the immune response. Results were confirmed at the protein level via detecting the levels of interleukin-2 （IL-2）, IL-6, IL-10, IL-12, leptin （LEP）, interferon-γ （IFN-γ）, transforming growth factor-βl （TGF-β1）, and tumor necrosis factor-α （TNF-α） in peripheral blood by enzyme-linked immunosorbent assay （ELISA） and radioimmunoassay analysis. Our data supported the conclusions that the protein content in milk of the MF group was higher than that of the CS group, the CS-based diets induced more release of cytokines than the MF-based diets in dairy cows＇ PBMCs, and milk protein content may be affected by cytokines.展开更多
OBJECTIVE： To observe effect of Liuweibuqi Capsule, a Traditional Chinese Medicine （TCM）, on the janus kinase （JAK）/signal transducer and activator of transcription （STAT） pathway and matrix metalloproteinases ...OBJECTIVE： To observe effect of Liuweibuqi Capsule, a Traditional Chinese Medicine （TCM）, on the janus kinase （JAK）/signal transducer and activator of transcription （STAT） pathway and matrix metalloproteinases （MMPs） in a chronic obstructive pulmonary disease （COPD） rat model with lung deficiency in terms of TCM＇s pattern differentiation. METHODS： Rats were randomly divided into a normal group, model group, Liuweibuqi group, Jinshuibao group, and spleen aminopeptidase group （n= 10）. Aside from the normal group, all rats were ex-posed to smoke plus lipopolysaccharide tracheal instillation to establish the COPD model with lung deficiency. Models were established after 28 days and then the normal and model groups were given normal saline （0.09 g/kg）, Liuweibuqi group was given Liuweibuqi capsule （0.35 g/kg）, Jinshuibao group was given Jinshuibao capsules （0.495 g/kg）, and the spleen group was given spleen aminopeptidase （0.33 mg/kg）, once a day for 30 days. Changes in symptoms, signs, and lung histology were observed. Lung function was measured with a spirometer. Serum cytokines were detected using enzyme-linked immunosorbent assay, and changes in the JAK/STAT pathway, MMP-9, and MMPs inhibitor 1 （TIMP1） were detected by immunohistochemistry, RT-PCR, and western blotting, respectively.RESULTS： Compared with the normal group, lung tissue was damaged, and lung function was reduced in the model control group. Additionally, the levels of interleukin （IL）-1β, y interferon （IFN-γ）, and IL-6 were higher, while IL-4 and IL-10 were lower in the model control group than those in the normal group. The expressions of JAK1, STAT3, ρ-STAT3, and MMP-9 mRNA and protein in lung tissue were higher, and TIMP1 mRNA and protein was lower in the model group compared with the normal group. After treatment, compared with the model group, the expression of inflammatory cytokines was lower in each treatment group, and expressions of JAK/ STAT pathway, MMPs were lower. Compared with the positive control groups, the Jinshuibao and spleen aminopeptidase groups, lung function was better, and JAK1, STAT3, and p-STAT3 protein were lower and TIMP1 was higher in the Liuweibuqi group.CONCLUSION： Liuweibuqi capsules can improve the symptoms of COPD possibly by regulating the expression of the JAK1/STAT3 pathway and MMP9/ TIMP1.展开更多
OBJECTIVE:To observe and compare the effects of Chinese herbal prescriptions for promoting blood circulation,clearing heat,removing toxicity,and dispersing stagnated liver-Qi on cytokines in model rats with experiment...OBJECTIVE:To observe and compare the effects of Chinese herbal prescriptions for promoting blood circulation,clearing heat,removing toxicity,and dispersing stagnated liver-Qi on cytokines in model rats with experimental autoimmune prostatitis(EAP) to provide an experimental basis for the use of Chinese herbal prescriptions in the treatment of chronic prostatitis.METHODS:One-hundred and ten male Wistar rats were randomly divided into 11 groups:blank group;model group;Huoxuehuayu(promoting blood circulation to remove blood stasis) high,middle,and low dose groups;Qingrejiedu(clearing heat and removing toxicity) high,middle,and low dose groups;and Shuganliqi(dispersing stagnated liver-Qi) high,middle,and low dose groups.Except the blank group,rats in all groups were injected subcutaneously in multiple points on days 0 and 30 with prostatic protein extractive solution(60 mg/ml_),and intraperitoneally injected with diphtheria-pertussis and tetanus vaccine(DPT vaccine) to establish the EAP model.Model rats were administrated high,middle,and low doses of Chinese herbal prescriptions and were sacrificed after 4 weeks.Pathological changes in the prostate gland were observed with HE staining and changes in serum interleukin-6(IL-6),interleukin-8(IL-8),and prostaglandin E_2(PGE_2) levels were detected with enzyme-linked immunosorbent assay.RESULTS:Compared with the blank group,serum PGE_2,IL-6,and IL-8 levels in the model group were significantly higher(P < 0.05).Compared with the model group,serum PGE_2,IL-6,and IL-8 levels in the Qingrejiedu low dose and middle dose groups were significantly lower(P < 0.05),with the lower dose having a more obvious effect.Serum PGE_2,IL-6,and IL-8 levels in the Huoxuehuayu high dose group(P < 0.05),IL-6 and IL-8 levels in the Huoxuehuayu middle dose group(P < 0.05),and the IL-8level in the Huoxuehuayu low dose group were significantly lower than those in the model group(P < 0.05).There were significant differences in PGE_2 and IL-6 levels among the different dose groups of Shuganliqi drugs(P < 0.05).Compared with the model group,serum PGE_(2/) IL-6,and IL-8levels in the Shuganliqi high dose group(P <0.05) and IL-8 level in the Shuganliqi low dose group were significantly lower(P < 0.05),while the Shuganliqi middle dose group did not change significantly(P > 0.05).CONCLUSION:Therefore,in TCM treatment of autoimmune prostatitis,different treatment methods should select different doses.For prescriptions that clear heat and remove toxicity,low doses should be used.For prescriptions that promote blood circulation to remove blood stasis and for prescriptions that disperse stagnated liver-Qi,high doses should be used.展开更多
文摘Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.
基金Supported by A research grant(DK-018777)from the National Institute of Diabetes and Digestive and Kidney Diseases
文摘Inflammatory bowel disease(IBD)is a common and lifelong disabling gastrointestinal disease.Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response.Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models.High extracellular adenosine suppresses and resolves chronic inflammation in IBD models.High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis.Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation. Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells,respectively. Increased extracellular adenosine levels activate the A2a receptor,which would reduce cytokines responsible for chronic inflammation.
基金Supported by National Institute of Health,NIH DK 43785
文摘Inflammatory bowel diseases(IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease.At the core of these alterations are endothelial cells,whose continual adjustments in structure and function coordinate vascular supply,immune cell emigration,and regulation of the tissue environment.Expansion of the endothelium in IBD(angiogenesis),mediated by inflammatory growth factors,cytokines and chemokines,is a hallmark of active gut disease and is closely related to disease severity.The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines,growth factors,and adhesion molecules,altering coagulant capacity,barrier function and blood cell recruitment in injury.This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.
文摘Toll-like receptors （TLRs） are probably the most important class of pattern-recognition receptors. Members of the TLR family play key roles in the both innate and adaptive immune responses. Recognition of pathogen-associated molecular patterns （PAMPs） by TLRs, either alone or in heterodimedzation with other TLR or non-TLR receptors, induces the production of signals that are responsible for the activation of genes important for an effective host defense, especially those of proinflammatory cytokines. Thus, TLRs are involved in the development of many pathological conditions including infectious diseases, tissue damage, and cancer especially. In this review, the contribution of TLRs to tumorgenesis is evaluated. We hope to provide new insight into the progression of cancer and more importantly into the potential for TLRs as targets of therapeutics.
基金Project supported by the National Natural Science Foundation of China(No.31772715)the National Basic Research Program(973)of China(No.2011CB100805)
文摘Recent studies have shown that diet can affect the body＇s immunity. Roughage of dairy cows consists of a variety of plant materials which make different contributions to health. This study investigated the effect of different roughages on the immunity of dairy cows. Serum, peripheral blood mononuclear cells （PBMCs）, and milk samples were collected from 20 multiparous mid-lactation cows fed mixed forage （MF）- or corn straw （CS）-based diets. Ex- pression profile analysis was used to detect the differentially expressed genes （DEGs） from PBMCs. The results showed that milk protein in the MF group increased to 3.22 g/100 ml, while that of the CS group milk was 2.96 g/100 ml; by RNA sequencing, it was found that 1615 genes were differentially expressed between the CS group and the MF group among the 24027 analyzed probes. Gene ontology （GO） and pathway analysis of DEGs suggested that these genes （especially genes coding cytokines, chemokine and its receptors） are involved in the immune response. Results were confirmed at the protein level via detecting the levels of interleukin-2 （IL-2）, IL-6, IL-10, IL-12, leptin （LEP）, interferon-γ （IFN-γ）, transforming growth factor-βl （TGF-β1）, and tumor necrosis factor-α （TNF-α） in peripheral blood by enzyme-linked immunosorbent assay （ELISA） and radioimmunoassay analysis. Our data supported the conclusions that the protein content in milk of the MF group was higher than that of the CS group, the CS-based diets induced more release of cytokines than the MF-based diets in dairy cows＇ PBMCs, and milk protein content may be affected by cytokines.
基金Supported by The National Natural Science Foundation Project:Study on the Metabolism of Chronic Obstructive Pulmonary Disease Pulmonary Qi Deficiency Syndrome and Cerebral Cortex Correlation Spectrum(No.81072781)
文摘OBJECTIVE： To observe effect of Liuweibuqi Capsule, a Traditional Chinese Medicine （TCM）, on the janus kinase （JAK）/signal transducer and activator of transcription （STAT） pathway and matrix metalloproteinases （MMPs） in a chronic obstructive pulmonary disease （COPD） rat model with lung deficiency in terms of TCM＇s pattern differentiation. METHODS： Rats were randomly divided into a normal group, model group, Liuweibuqi group, Jinshuibao group, and spleen aminopeptidase group （n= 10）. Aside from the normal group, all rats were ex-posed to smoke plus lipopolysaccharide tracheal instillation to establish the COPD model with lung deficiency. Models were established after 28 days and then the normal and model groups were given normal saline （0.09 g/kg）, Liuweibuqi group was given Liuweibuqi capsule （0.35 g/kg）, Jinshuibao group was given Jinshuibao capsules （0.495 g/kg）, and the spleen group was given spleen aminopeptidase （0.33 mg/kg）, once a day for 30 days. Changes in symptoms, signs, and lung histology were observed. Lung function was measured with a spirometer. Serum cytokines were detected using enzyme-linked immunosorbent assay, and changes in the JAK/STAT pathway, MMP-9, and MMPs inhibitor 1 （TIMP1） were detected by immunohistochemistry, RT-PCR, and western blotting, respectively.RESULTS： Compared with the normal group, lung tissue was damaged, and lung function was reduced in the model control group. Additionally, the levels of interleukin （IL）-1β, y interferon （IFN-γ）, and IL-6 were higher, while IL-4 and IL-10 were lower in the model control group than those in the normal group. The expressions of JAK1, STAT3, ρ-STAT3, and MMP-9 mRNA and protein in lung tissue were higher, and TIMP1 mRNA and protein was lower in the model group compared with the normal group. After treatment, compared with the model group, the expression of inflammatory cytokines was lower in each treatment group, and expressions of JAK/ STAT pathway, MMPs were lower. Compared with the positive control groups, the Jinshuibao and spleen aminopeptidase groups, lung function was better, and JAK1, STAT3, and p-STAT3 protein were lower and TIMP1 was higher in the Liuweibuqi group.CONCLUSION： Liuweibuqi capsules can improve the symptoms of COPD possibly by regulating the expression of the JAK1/STAT3 pathway and MMP9/ TIMP1.
基金Supported by Natural Science Foundation of China(Research on Molecular Biological Mechanisms of the Three Methods,Promoting Blood Circulation to Remove Blood Stasis,Dispersing Stagnated Liver-Qi,and Clearing Heat and Removing Toxicity,for Treatment of Neuralgia Induced by Chronic Prostatitis,No.81060321)
文摘OBJECTIVE:To observe and compare the effects of Chinese herbal prescriptions for promoting blood circulation,clearing heat,removing toxicity,and dispersing stagnated liver-Qi on cytokines in model rats with experimental autoimmune prostatitis(EAP) to provide an experimental basis for the use of Chinese herbal prescriptions in the treatment of chronic prostatitis.METHODS:One-hundred and ten male Wistar rats were randomly divided into 11 groups:blank group;model group;Huoxuehuayu(promoting blood circulation to remove blood stasis) high,middle,and low dose groups;Qingrejiedu(clearing heat and removing toxicity) high,middle,and low dose groups;and Shuganliqi(dispersing stagnated liver-Qi) high,middle,and low dose groups.Except the blank group,rats in all groups were injected subcutaneously in multiple points on days 0 and 30 with prostatic protein extractive solution(60 mg/ml_),and intraperitoneally injected with diphtheria-pertussis and tetanus vaccine(DPT vaccine) to establish the EAP model.Model rats were administrated high,middle,and low doses of Chinese herbal prescriptions and were sacrificed after 4 weeks.Pathological changes in the prostate gland were observed with HE staining and changes in serum interleukin-6(IL-6),interleukin-8(IL-8),and prostaglandin E_2(PGE_2) levels were detected with enzyme-linked immunosorbent assay.RESULTS:Compared with the blank group,serum PGE_2,IL-6,and IL-8 levels in the model group were significantly higher(P < 0.05).Compared with the model group,serum PGE_2,IL-6,and IL-8 levels in the Qingrejiedu low dose and middle dose groups were significantly lower(P < 0.05),with the lower dose having a more obvious effect.Serum PGE_2,IL-6,and IL-8 levels in the Huoxuehuayu high dose group(P < 0.05),IL-6 and IL-8 levels in the Huoxuehuayu middle dose group(P < 0.05),and the IL-8level in the Huoxuehuayu low dose group were significantly lower than those in the model group(P < 0.05).There were significant differences in PGE_2 and IL-6 levels among the different dose groups of Shuganliqi drugs(P < 0.05).Compared with the model group,serum PGE_(2/) IL-6,and IL-8levels in the Shuganliqi high dose group(P <0.05) and IL-8 level in the Shuganliqi low dose group were significantly lower(P < 0.05),while the Shuganliqi middle dose group did not change significantly(P > 0.05).CONCLUSION:Therefore,in TCM treatment of autoimmune prostatitis,different treatment methods should select different doses.For prescriptions that clear heat and remove toxicity,low doses should be used.For prescriptions that promote blood circulation to remove blood stasis and for prescriptions that disperse stagnated liver-Qi,high doses should be used.
