BACKGROUND Ischemia-reperfusion injury(IRI) is a major risk associated with liver surgery and transplantation,and its pathological mechanism is complex.Interleukin-1 receptor antagonist(IL-1ra) can protect the liver f...BACKGROUND Ischemia-reperfusion injury(IRI) is a major risk associated with liver surgery and transplantation,and its pathological mechanism is complex.Interleukin-1 receptor antagonist(IL-1ra) can protect the liver from IRI.However,the regulatory mechanism of IL-1ra expression is still unclear.AIM To identify the mechanism that could protect the liver in the early stage of IRI.METHODS To screen the key genes in hepatic IRI,we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI.Subsequently,we verified the expression and effect of IL-1ra in hepatic IRI.We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor(HIF)-1α.Finally,to explore the protective mechanism of ischemic preconditioning(IP),we examined the expression of HIF-1α and IL-1ra after IP.RESULTS We identified IL-1ra as a key regulator in hepatic IRI.The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro.Furthermore,we found that HIF-1αregulated Il-1ra transcription in response to hypoxia.Increased HIF-1α accumulation promoted IL-1ra expression,whereas inhibition of HIF-1α exhibited the opposite effect.We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1αactivation.Of note,we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression,which is mediated through HIF-1α.CONCLUSION We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α.Importantly,IP protects the liver from IRI via the HIF-1α–IL-1ra pathway.展开更多
Gene therapy constitutes a promising strategy for the treatment of osteoarthritis (OA). We assessed the use of electroporation (EP) of non-viral gene vectors, and compared its efficacy with that of adeno-associated vi...Gene therapy constitutes a promising strategy for the treatment of osteoarthritis (OA). We assessed the use of electroporation (EP) of non-viral gene vectors, and compared its efficacy with that of adeno-associated virus (AAV) vectors. EP- and AAV-mediated delivery of human interleukin-1 receptor antagonist (hIL-1Ra) was localized performed in the joints of rats following induction of OA. mRNA levels for hIL-1Ra, IL-1β, TNF-α, MMP-13 and ADAMTS-4 in the cartilage and synovial tissues were analyzed. Structural analyses of the subchondral bone at the medial femoral condyle were performed by Micro-CT after treatment. Knee joint specimens were staining with hematoxylin and eosin and Saffron O. Induction of hIL-1Ra by both EP and AAV inhibited inflammatory-induced sub-chondral bone reconstruction, and effectively suppressed IL-1β activity, as evidenced by decreased expression of MMP-13 and ADAMTS-4. Histological analyses revealed significant protection of cartilage, proteoglycan by EP and AAV. hIL-1Ra expression was similar in both the EP and AAV groups. Notably, this gene is not easier degraded transduced by EP compared with AAV. Taken together, these results show that EP offers transfection efficiency comparable to that of AAV, with the potential for longer gene expression, making EP a promising candidate for efficient non-viral delivery of OA gene therapy.展开更多
AIM: To study the efficacy of marrow mesenchymal stem cells (MSCs) transplantation combined with interleukin-1 receptor antagonist (IL-1Ra) for acute liver failure (ALF). METHODS: Chinese experimental miniature swine ...AIM: To study the efficacy of marrow mesenchymal stem cells (MSCs) transplantation combined with interleukin-1 receptor antagonist (IL-1Ra) for acute liver failure (ALF). METHODS: Chinese experimental miniature swine were randomly divided into four groups (n = 7), and all animals were given D-galactosamine (D-gal) to induce ALF. Group A animals were then injected with 40 mL saline via the portal vein 24 h after D-gal induction;Group B animals were injected with 2 mg/kg IL-1Ra via the ear vein 18 h, 2 d and 4 d after D-gal induction; Group C received approximately 1 × 108 green fluorescence protein (GFP)-labeled MSCs (GFP-MSCs) suspended in 40 mL normal saline via the portal vein 24 h after D-gal induction; Group D animals were injected with 2 mg/kg IL-1Ra via the ear vein 18 h after D-gal induction, MSCs transplantation was then carried out at 24 h after D-gal induction, and finally 2 mg/kg IL-1Ra was injected via the ear vein 1 d and 3 d after surgery as before. Liver function, serum inflammatory parameters and pathological changes were measured and the fate of MSCs was determined.RESULTS: The optimal efficiency of transfection (97%) was achieved at an multiplicity of infection of 80, as observed by fluorescence microscopy and flow cytometry (FCM). Over 90% of GFP-MSCs were identified as CD44+ CD90+ CD45-MSCs by FCM, which indicated that most GFP-MSCs retained MSCs characteristics. Biochemical assays, the levels of serum inflammatory parameters and histological results in Group D all showed a significant improvement in liver injury compared with the other groups (P < 0.05). The number of GFP-MSCs in Group D was also greater than that in Group B, and the long-term cell proliferation rate was also better in Group D than in the other groups.CONCLUSION: MSCs transplantation is useful in ALF, IL-1Ra plays an important role in alleviating the inflammatory condition, and combination therapy with MSCs transplantation and IL-1Ra is a promising treatment for ALF.展开更多
Objective To identify an interaction between the interleukin-1 receptor antagonist gene polymorphism and risk of Al-zheimer’s disease. Methods The study included 117 healthy controls, 85 patients with Alzheimer’s di...Objective To identify an interaction between the interleukin-1 receptor antagonist gene polymorphism and risk of Al-zheimer’s disease. Methods The study included 117 healthy controls, 85 patients with Alzheimer’s disease in a Northeastern Chinese popu-lation of Han nationality. Genotypes were determined by a polymerase chain reaction amplification of the intron 2 fragment, harbouring a variable number of short tandem nucleotide sequences. Amplification products were separated on a 2% agarose gel. Results The allele 2 frequency was 27% in healthy controls, and 21% in patients with Alzheimer’s disease. Thus for all-ele 2 as well as for all other alleles, genotypes, or carriage rates, no significant differences compared with controls. Conclusions No association of interleukin-1 receptor antagonist gene polymorphism with Alzheimer’s disease was iden-tified in this population. It is also possible that the increased risk and disease modifying effects are caused by linkage disequ-ilibrium with other genomic variants in other nearby genes.展开更多
The course and severity of periodontitis can be significantly affected by bacterial virulence as well as host immunity dysfunction. Periodontal tissue destruction has been proved to result from cascade of cytokines sy...The course and severity of periodontitis can be significantly affected by bacterial virulence as well as host immunity dysfunction. Periodontal tissue destruction has been proved to result from cascade of cytokines synthesized by reactive cells upon stimulation by pathogenic bacteria and lipopolysaccharides within their cell membranes. The clinical use of genetically programmed cells, producing substances blocking IL-1, based on recombinant IL-1 antagonist, as well as cytokines activating fibroblasts and osteoblasts to regenerate the destroyed periodontal tissue could prove alternative to the conventional treatment. Another cytokine of interest in respect to periodontitis ethiopathogenesis is soluble tumor necrosis factor receptor I (sTNF RI). Observation of soluble TNF receptors as physiologic inhibitors of TNF led to its administration in therapeutic process as well as in therapy selected cases of aggressive periodontitis.展开更多
The immunoregulating effect of Interleukin-1-receptor antagonist (ILlra ) in lupus-like NZB/W F, mice was investigated to find possible approach to prevent lupus nephritis. 12 female NZB/W F1 mice of 13 weeks were ran...The immunoregulating effect of Interleukin-1-receptor antagonist (ILlra ) in lupus-like NZB/W F, mice was investigated to find possible approach to prevent lupus nephritis. 12 female NZB/W F1 mice of 13 weeks were randomly divlded into 2 groups. Each mouse in the treated group was intraperitoneally injected wlth IL-lra once every 2 weeks for 3 times at the dosage of 100μg each time,while the control group was given injection of 0.1 ml normal saline. All the mice were killed at the age of 9 months and the irnmunologic function was examined.Results showed that this dosage could not completely prevent the development of lupus nephritis, but the renal damage was alleviated and the urine protein was decreased. Moreover, it could improve the immunofunction by significantly reducing the levels of serum IL-1 and obviously increase the activities of NK celIs and IL-2 induced by ConA in mononuclear cells of spleen. There was no significant difference in the levels of serum IL-6 and TNF-α between the treated group and control group. It is concluded that IL-lra has certain regulatory effect on the immunologic function of lupus-like NZB/W F, mice.展开更多
Background Immune rejection is the main reason of grafts failure after corneal transplantation. This study was to determine whether interlerkin-1 receptor antagonist (IL-1ra) eye drops could prolong corneal allografts...Background Immune rejection is the main reason of grafts failure after corneal transplantation. This study was to determine whether interlerkin-1 receptor antagonist (IL-1ra) eye drops could prolong corneal allografts survival in high-risk corneal orthotopic allotransplantation in rat model and to study the effect of IL-1ra on the expression of CD 1-positive cells in the grafts Methods For all experiments, the Sprague-Dawley (SD) rats’ corneas were transplanted into Wistar rats’ eyes High-risk transplants included those that had been sutured into Wistar recipient beds with corneal neovascularization induced by placement of three interrupted sutures in the host cornea 7 days earlier All the animals were divided, in a masked fashion, into three treatment groups and one control group Each treatment group received IL-1ra eye drops of different concentrations (1 mg/ml, 3 mg/ml, or 5 mg/ml, respectively) four times a day for 30 days The control group received 0 9% normal saline (NS) eye drops in the same way as the treatment groups All allografts were evaluated for signs of rejection from the first day after surgery Ten days later, corneal specimens were processed to examine the expression of CD 1-positive cells and histopathological changes Results The survival time of the transplants was 5 80±0 79, 5 89±1 05, 6 78±0 83, and 9 00±2 36 days respectively in the control or three treatment groups Compared with the control group, 1 mg/ml IL-1ra eye drop did not prolong the survival time of the allografts ( t =0 210, P >0 05) However, 3 mg/ml and 5 mg/ml IL-1ra eye drop did prolong the survival time of the grafts ( t ≥2.627, P <0 05), with the latter showing more obvious effect Immunohistochemical examinations showed a significant decrease in inflammatory cell and CD 1-positive cell infiltration in IL-1ra treated groups compared with the control group Conclusions IL-1ra can promote corneal allograft survival in a dose-dependant manner by reducing the infiltration of CD 1-positive cells in high-risk corneal展开更多
Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy.Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammati...Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy.Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth.Multiple pathways are involved in the pathogenesis of perinatal inflammation.However,studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1.In this review,we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury.We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage,and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist,anakinra,as a safe and effective therapeutic intervention.We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment,and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.展开更多
AIM: To study the therapeutic effects of mesenchymal stem cells(MSCs) and an interleukin-1 receptor antagonist(IL-1Ra) in acute liver failure. METHODS: Chinese experimental miniature swine(15 ± 3 kg, 5-8 mo) were...AIM: To study the therapeutic effects of mesenchymal stem cells(MSCs) and an interleukin-1 receptor antagonist(IL-1Ra) in acute liver failure. METHODS: Chinese experimental miniature swine(15 ± 3 kg, 5-8 mo) were obtained from the Laboratory Animal Centre of the Affiliated Drum Tower Hospital of Nanjing University Medical School. Acute liver failure was induced via 85% hepatectomy, and animals were treated by MSC transplantation combined with IL-1Ra injection. Blood samples were collected for hepatic function analysis, and the living conditions and survival time were recorded. Liver injury was histologically analyzed. Hepatic cell regeneration and apoptosis were studied by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase d UTP nick end labeling, respectively. The levels of protein kinase B and nuclear factor-κB expression were analyzed by Western blotting.RESULTS: MSCs were infected with a lentivirus for expression of green fluorescent protein(GFP) for subsequent identification; 97.3% of the MSCs were positive for GFP as assessed by flow cytometry.Additional flow cytometric analysis of cell surface marker expression demonstrated that > 90% of GFP-expressing MSCs were also positive for CD29, CD44, and CD90, indicating that most of these cells expressed typical markers of MSCs, and the population of MSCs was almost pure. Transplantation of MSCs in combination with 2 mg/kg IL-1Ra therapy significantly improved survival time compared to the acute liver failure model group(35.3 ± 6.7 d vs 17.3 ± 5.5 d, P < 0.05). Combined therapy also promoted improvement in serum inflammatory cytokines and biochemical conditions. The observed hepatic histopathologic score was significantly lower in the group with combined therapy than in the model group(3.50 ± 0.87 vs 8.17 ± 1.26, P < 0.01). In addition, liver cell apoptosis in the combined therapy group was significantly inhibited(18.1 ± 2.1% vs 70.8 ± 3.7%, P < 0.01), and hepatic cell regeneration increased. A significant increase in protein kinase B expression and decrease in nuclear factor-κB expression were observed(P < 0.01), which supports their important roles in liver regeneration.CONCLUSION: MSCs and IL-1Ra had a synergistic effect in liver regeneration via regulation of inflammation and apoptotic signaling.展开更多
AIM:To study the association between Interleukin-1(IL-1)and tumor necrosis factor(TNF)-αpolymorphisms,infection by Helicobacter pylori(H pylori)and the development of gastrointestinal diseases.METHODS:Genomic DNA was...AIM:To study the association between Interleukin-1(IL-1)and tumor necrosis factor(TNF)-αpolymorphisms,infection by Helicobacter pylori(H pylori)and the development of gastrointestinal diseases.METHODS:Genomic DNA was extracted from the peripheral blood of 177 patients with various gastrointestinal diseases and from 100 healthy volunteers.The polymorphisms in IL-1βand TNF-αgenes were analyzed using the polymerase chain reactionrestriction fragment length polymorphism method(PCRRFLP)and those from IL-1RN with PCR.The presence of infection due to H pylori and the presence of the CagA toxin were detected by serology.The histopathological parameters in the gastric biopsies of the patients were according to the Sydney classification.RESULTS:A comparison of the frequencies of the different polymorphisms studied among the patients and the control group demonstrated that the allele IL1RN*2 was more frequent among patients with gastric ulcers and adenocarcinoma.Carriers of the allele ILRN*2 and those with reactive serology for anti-CagA IgG had a greater risk of developing peptic ulcer and gastric adenocarcinoma,as well as a higher degree of inflammation and neutrophilic activity in the gastric mucosa.CONCLUSION:Our results indicate a positive association between IL-1RN gene polymorphism and infection by positive H pylori CagA strains and the development of gastric ulcers and adenocarcinoma.展开更多
基金the National Natural Science Foundation of China,No.81670600.
文摘BACKGROUND Ischemia-reperfusion injury(IRI) is a major risk associated with liver surgery and transplantation,and its pathological mechanism is complex.Interleukin-1 receptor antagonist(IL-1ra) can protect the liver from IRI.However,the regulatory mechanism of IL-1ra expression is still unclear.AIM To identify the mechanism that could protect the liver in the early stage of IRI.METHODS To screen the key genes in hepatic IRI,we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI.Subsequently,we verified the expression and effect of IL-1ra in hepatic IRI.We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor(HIF)-1α.Finally,to explore the protective mechanism of ischemic preconditioning(IP),we examined the expression of HIF-1α and IL-1ra after IP.RESULTS We identified IL-1ra as a key regulator in hepatic IRI.The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro.Furthermore,we found that HIF-1αregulated Il-1ra transcription in response to hypoxia.Increased HIF-1α accumulation promoted IL-1ra expression,whereas inhibition of HIF-1α exhibited the opposite effect.We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1αactivation.Of note,we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression,which is mediated through HIF-1α.CONCLUSION We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α.Importantly,IP protects the liver from IRI via the HIF-1α–IL-1ra pathway.
文摘Gene therapy constitutes a promising strategy for the treatment of osteoarthritis (OA). We assessed the use of electroporation (EP) of non-viral gene vectors, and compared its efficacy with that of adeno-associated virus (AAV) vectors. EP- and AAV-mediated delivery of human interleukin-1 receptor antagonist (hIL-1Ra) was localized performed in the joints of rats following induction of OA. mRNA levels for hIL-1Ra, IL-1β, TNF-α, MMP-13 and ADAMTS-4 in the cartilage and synovial tissues were analyzed. Structural analyses of the subchondral bone at the medial femoral condyle were performed by Micro-CT after treatment. Knee joint specimens were staining with hematoxylin and eosin and Saffron O. Induction of hIL-1Ra by both EP and AAV inhibited inflammatory-induced sub-chondral bone reconstruction, and effectively suppressed IL-1β activity, as evidenced by decreased expression of MMP-13 and ADAMTS-4. Histological analyses revealed significant protection of cartilage, proteoglycan by EP and AAV. hIL-1Ra expression was similar in both the EP and AAV groups. Notably, this gene is not easier degraded transduced by EP compared with AAV. Taken together, these results show that EP offers transfection efficiency comparable to that of AAV, with the potential for longer gene expression, making EP a promising candidate for efficient non-viral delivery of OA gene therapy.
基金Supported by National Natural Science Foundation of China,No. 30901431
文摘AIM: To study the efficacy of marrow mesenchymal stem cells (MSCs) transplantation combined with interleukin-1 receptor antagonist (IL-1Ra) for acute liver failure (ALF). METHODS: Chinese experimental miniature swine were randomly divided into four groups (n = 7), and all animals were given D-galactosamine (D-gal) to induce ALF. Group A animals were then injected with 40 mL saline via the portal vein 24 h after D-gal induction;Group B animals were injected with 2 mg/kg IL-1Ra via the ear vein 18 h, 2 d and 4 d after D-gal induction; Group C received approximately 1 × 108 green fluorescence protein (GFP)-labeled MSCs (GFP-MSCs) suspended in 40 mL normal saline via the portal vein 24 h after D-gal induction; Group D animals were injected with 2 mg/kg IL-1Ra via the ear vein 18 h after D-gal induction, MSCs transplantation was then carried out at 24 h after D-gal induction, and finally 2 mg/kg IL-1Ra was injected via the ear vein 1 d and 3 d after surgery as before. Liver function, serum inflammatory parameters and pathological changes were measured and the fate of MSCs was determined.RESULTS: The optimal efficiency of transfection (97%) was achieved at an multiplicity of infection of 80, as observed by fluorescence microscopy and flow cytometry (FCM). Over 90% of GFP-MSCs were identified as CD44+ CD90+ CD45-MSCs by FCM, which indicated that most GFP-MSCs retained MSCs characteristics. Biochemical assays, the levels of serum inflammatory parameters and histological results in Group D all showed a significant improvement in liver injury compared with the other groups (P < 0.05). The number of GFP-MSCs in Group D was also greater than that in Group B, and the long-term cell proliferation rate was also better in Group D than in the other groups.CONCLUSION: MSCs transplantation is useful in ALF, IL-1Ra plays an important role in alleviating the inflammatory condition, and combination therapy with MSCs transplantation and IL-1Ra is a promising treatment for ALF.
基金Supported by a grant from the Heilongjiang Provincial Natural Science Foundation (D01-21) and partly by the National Postdoctoral Research Foundation (LRB 00071).
文摘Objective To identify an interaction between the interleukin-1 receptor antagonist gene polymorphism and risk of Al-zheimer’s disease. Methods The study included 117 healthy controls, 85 patients with Alzheimer’s disease in a Northeastern Chinese popu-lation of Han nationality. Genotypes were determined by a polymerase chain reaction amplification of the intron 2 fragment, harbouring a variable number of short tandem nucleotide sequences. Amplification products were separated on a 2% agarose gel. Results The allele 2 frequency was 27% in healthy controls, and 21% in patients with Alzheimer’s disease. Thus for all-ele 2 as well as for all other alleles, genotypes, or carriage rates, no significant differences compared with controls. Conclusions No association of interleukin-1 receptor antagonist gene polymorphism with Alzheimer’s disease was iden-tified in this population. It is also possible that the increased risk and disease modifying effects are caused by linkage disequ-ilibrium with other genomic variants in other nearby genes.
文摘The course and severity of periodontitis can be significantly affected by bacterial virulence as well as host immunity dysfunction. Periodontal tissue destruction has been proved to result from cascade of cytokines synthesized by reactive cells upon stimulation by pathogenic bacteria and lipopolysaccharides within their cell membranes. The clinical use of genetically programmed cells, producing substances blocking IL-1, based on recombinant IL-1 antagonist, as well as cytokines activating fibroblasts and osteoblasts to regenerate the destroyed periodontal tissue could prove alternative to the conventional treatment. Another cytokine of interest in respect to periodontitis ethiopathogenesis is soluble tumor necrosis factor receptor I (sTNF RI). Observation of soluble TNF receptors as physiologic inhibitors of TNF led to its administration in therapeutic process as well as in therapy selected cases of aggressive periodontitis.
文摘The immunoregulating effect of Interleukin-1-receptor antagonist (ILlra ) in lupus-like NZB/W F, mice was investigated to find possible approach to prevent lupus nephritis. 12 female NZB/W F1 mice of 13 weeks were randomly divlded into 2 groups. Each mouse in the treated group was intraperitoneally injected wlth IL-lra once every 2 weeks for 3 times at the dosage of 100μg each time,while the control group was given injection of 0.1 ml normal saline. All the mice were killed at the age of 9 months and the irnmunologic function was examined.Results showed that this dosage could not completely prevent the development of lupus nephritis, but the renal damage was alleviated and the urine protein was decreased. Moreover, it could improve the immunofunction by significantly reducing the levels of serum IL-1 and obviously increase the activities of NK celIs and IL-2 induced by ConA in mononuclear cells of spleen. There was no significant difference in the levels of serum IL-6 and TNF-α between the treated group and control group. It is concluded that IL-lra has certain regulatory effect on the immunologic function of lupus-like NZB/W F, mice.
文摘Background Immune rejection is the main reason of grafts failure after corneal transplantation. This study was to determine whether interlerkin-1 receptor antagonist (IL-1ra) eye drops could prolong corneal allografts survival in high-risk corneal orthotopic allotransplantation in rat model and to study the effect of IL-1ra on the expression of CD 1-positive cells in the grafts Methods For all experiments, the Sprague-Dawley (SD) rats’ corneas were transplanted into Wistar rats’ eyes High-risk transplants included those that had been sutured into Wistar recipient beds with corneal neovascularization induced by placement of three interrupted sutures in the host cornea 7 days earlier All the animals were divided, in a masked fashion, into three treatment groups and one control group Each treatment group received IL-1ra eye drops of different concentrations (1 mg/ml, 3 mg/ml, or 5 mg/ml, respectively) four times a day for 30 days The control group received 0 9% normal saline (NS) eye drops in the same way as the treatment groups All allografts were evaluated for signs of rejection from the first day after surgery Ten days later, corneal specimens were processed to examine the expression of CD 1-positive cells and histopathological changes Results The survival time of the transplants was 5 80±0 79, 5 89±1 05, 6 78±0 83, and 9 00±2 36 days respectively in the control or three treatment groups Compared with the control group, 1 mg/ml IL-1ra eye drop did not prolong the survival time of the allografts ( t =0 210, P >0 05) However, 3 mg/ml and 5 mg/ml IL-1ra eye drop did prolong the survival time of the grafts ( t ≥2.627, P <0 05), with the latter showing more obvious effect Immunohistochemical examinations showed a significant decrease in inflammatory cell and CD 1-positive cell infiltration in IL-1ra treated groups compared with the control group Conclusions IL-1ra can promote corneal allograft survival in a dose-dependant manner by reducing the infiltration of CD 1-positive cells in high-risk corneal
基金supported by the CJ Martin Postdoctoral Fellowshipgrants from the National Health and Medical Research Council of Australia (1090890 and 1164954)+1 种基金the Cerebral Palsy Alliance, Harold and Cora Brennen Benevolent Trust, Health Research Council of New Zealand (17/601)the Victorian Government’s Operational Infrastructure Support Program (to RG)
文摘Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy.Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth.Multiple pathways are involved in the pathogenesis of perinatal inflammation.However,studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1.In this review,we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury.We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage,and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist,anakinra,as a safe and effective therapeutic intervention.We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment,and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.
基金Supported by The National Natural Science Foundation of China,No.81300338863 National Science and Technology Plans,No.2013aa020102Project Fund of Clinical Medical Center of Digestive Diseases in Jiangsu Province,No.bl2012001
文摘AIM: To study the therapeutic effects of mesenchymal stem cells(MSCs) and an interleukin-1 receptor antagonist(IL-1Ra) in acute liver failure. METHODS: Chinese experimental miniature swine(15 ± 3 kg, 5-8 mo) were obtained from the Laboratory Animal Centre of the Affiliated Drum Tower Hospital of Nanjing University Medical School. Acute liver failure was induced via 85% hepatectomy, and animals were treated by MSC transplantation combined with IL-1Ra injection. Blood samples were collected for hepatic function analysis, and the living conditions and survival time were recorded. Liver injury was histologically analyzed. Hepatic cell regeneration and apoptosis were studied by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase d UTP nick end labeling, respectively. The levels of protein kinase B and nuclear factor-κB expression were analyzed by Western blotting.RESULTS: MSCs were infected with a lentivirus for expression of green fluorescent protein(GFP) for subsequent identification; 97.3% of the MSCs were positive for GFP as assessed by flow cytometry.Additional flow cytometric analysis of cell surface marker expression demonstrated that > 90% of GFP-expressing MSCs were also positive for CD29, CD44, and CD90, indicating that most of these cells expressed typical markers of MSCs, and the population of MSCs was almost pure. Transplantation of MSCs in combination with 2 mg/kg IL-1Ra therapy significantly improved survival time compared to the acute liver failure model group(35.3 ± 6.7 d vs 17.3 ± 5.5 d, P < 0.05). Combined therapy also promoted improvement in serum inflammatory cytokines and biochemical conditions. The observed hepatic histopathologic score was significantly lower in the group with combined therapy than in the model group(3.50 ± 0.87 vs 8.17 ± 1.26, P < 0.01). In addition, liver cell apoptosis in the combined therapy group was significantly inhibited(18.1 ± 2.1% vs 70.8 ± 3.7%, P < 0.01), and hepatic cell regeneration increased. A significant increase in protein kinase B expression and decrease in nuclear factor-κB expression were observed(P < 0.01), which supports their important roles in liver regeneration.CONCLUSION: MSCs and IL-1Ra had a synergistic effect in liver regeneration via regulation of inflammation and apoptotic signaling.
基金Supported by Secretaria Executiva de Ciência,Tecnologiae Meio Ambiente-SECTAM and Coordenao de Aperfeioamento de Pessoal de Nível Superior-CAPES
文摘AIM:To study the association between Interleukin-1(IL-1)and tumor necrosis factor(TNF)-αpolymorphisms,infection by Helicobacter pylori(H pylori)and the development of gastrointestinal diseases.METHODS:Genomic DNA was extracted from the peripheral blood of 177 patients with various gastrointestinal diseases and from 100 healthy volunteers.The polymorphisms in IL-1βand TNF-αgenes were analyzed using the polymerase chain reactionrestriction fragment length polymorphism method(PCRRFLP)and those from IL-1RN with PCR.The presence of infection due to H pylori and the presence of the CagA toxin were detected by serology.The histopathological parameters in the gastric biopsies of the patients were according to the Sydney classification.RESULTS:A comparison of the frequencies of the different polymorphisms studied among the patients and the control group demonstrated that the allele IL1RN*2 was more frequent among patients with gastric ulcers and adenocarcinoma.Carriers of the allele ILRN*2 and those with reactive serology for anti-CagA IgG had a greater risk of developing peptic ulcer and gastric adenocarcinoma,as well as a higher degree of inflammation and neutrophilic activity in the gastric mucosa.CONCLUSION:Our results indicate a positive association between IL-1RN gene polymorphism and infection by positive H pylori CagA strains and the development of gastric ulcers and adenocarcinoma.
