白介素-1受体拮抗剂的抗炎性疼痛作用

白介素 1受体拮抗剂是白介素 1的内源性拮抗剂 ,能很好地阻断白介素 1与其受体的结合。它是一种急性期蛋白 ,可阻断鞘内及脑室注射白介素 1β对正常和炎性疼痛大鼠的致痛敏作用 ,可抑制强啡肽诱导的痛觉超敏 ,可明显减轻类风湿性关节炎的疼痛和炎症反应 ,可抑制脚掌注射角叉菜胶、脂多糖、缓激肽、肿瘤坏死因子 α、白介素 1β和醋酸等引起的炎性痛敏反应 ,在中枢和外周都起到很好的抗炎性疼痛作用。

白介素-1和银屑病

银屑病的发病机制至今尚未完全明确,银屑病皮损中存在细胞因子的异常表达。IL-1是重要的炎症递质,在银屑病皮损中IL-1表达异常。研究表明,IL-1在银屑病发病中起重要作用。

白介素-1受体拮抗剂对BXSB狼疮小鼠的治疗作用观察

利用基因工程技术获得高纯度人白介素-1受体拮抗剂（IL－1ra），连续性尾静脉注射4．5月龄雄性BXSB狼疮小鼠，发现其尿蛋白水平和ANA滴度的增加幅度减少，肾脏IgG、C3沉积减轻，血清白细胞介素-6（IL－6）活性和肾脏IL－6蛋白表达减弱。提示IL－1在BXSB狼疮小鼠发病中的病理性作用及IL－1ra对该鼠可能的治疗作用。

中耳乳突炎HRCT表现及其与IL-1相关性研究

目的 :探讨慢性中耳乳突炎的HRCT特征及IL 1在慢性中耳乳突炎中引起骨破坏的作用 ,旨在提高对各型慢性中耳乳突炎的诊断水平。方法 :对 4 8例慢性中耳乳突炎患者 ,行HRCT扫描 ,并与手术病理结果对照分析 ,采用放射免疫分析法检测IL 1在 4 8例慢性中耳乳突炎组织中及患者血清中含量 ,并与 6例正常皮肤组织及 30例正常血清中含量比较。结果 :①高分辨率CT显示胆脂瘤病变大多呈团块状病变 ,常伴有明显的听骨破坏和盾板骨质破坏 ;单纯型、肉芽肿型多数呈片状、条索状或网状病变 ,听骨破坏相对轻 ,少有盾板骨质破坏。②IL 1在中耳乳突炎中表达率为 10 0 % ,与正常皮肤组织、肉芽肿组织相比 ,胆脂瘤组织中IL 1过度表达 ,差异有显著性意义 (P <0 .0 1)。胆脂瘤组织中IL 1与胆脂瘤的骨质破坏程度高度相关 (r =0 .917,P <0 .0 1)。结论 :根据中耳腔软组织影的形态及骨质破坏而非病变的密度改变 ,大多数中耳乳突炎患者可籍HRCT扫描准确诊断 ;组织中IL 1与胆脂瘤型中耳乳突炎CT上骨质破坏程度高度相关 ,IL 1在胆脂瘤中的过度表达是中耳乳突炎导致骨破坏最重要因素之一。

Interleukin-1 beta up-regulates tissue inhibitor of matrix metalloproteinase-1 mRNA and phosphorylation of c-jun N-terminal kinase and p38 in hepatic stellate cells

AIM： To study the relationship between interleukin-lbeta （IL-1β） up-regulating tissue inhibitor of matrix metalloproteinase-1 （TIMMP-1） mRNA expression and phosphorylation of both c-jun N-terminal kinase （INK） and p38 in rat heffatic stellate cells （HSC）. METHODS： RT-PCR was performed to measure the expression of TIMMP-1 mRNA in rat HSC. Western blot was performed to measure IL-1β-induced JNK and p38 activities in rat HSC. RESULTS： TIMMP-1 mRNA expression （1.191± 0.079） was much higher after treatment with IL-1β （10 ng/mL） for 24 h than in control group （0.545±0.091） （P〈0.01）. IL-1β activated INK and p38 in a time-dependent manner. After stimulation with IL-1β for 0, 5, 15, 30, 60 and 120 min, the INK activity was 0.982±0.299, 1.501±0.720, 2.133±0.882, 3.360±0.452, 2.181±0.789, and 1.385 ± 0.368, respectively. There was a significant difference in JNK activity at 15 min （P〈 0.01）, 30 min （P〈 0.01） and 60 min （P〈0.01） in comparison to that at 0 min. The p38 activity was 1.061±0.310, 2.050±0.863, 2.380±0.573, 2.973±0.953, 2.421±0.793, and 1.755 ± 0.433 at the 6 time points （0, 5, 15, 30, 60 and 120 min） respectively. There was a significant difference in p38 activity at 5 min （P〈0.05）, 15 min （P〈0.01）, 30 min （P〈0.01） and 60 min （P〈0.01） compared to that at 0 min. TIMMP-1 mRNA expression trended to decrease in 3 groups pretreated with different concentrations of SP600125 （10 μmol/L, 1.022±0.113; 20 μmol/L, 0.869±0.070; 40 μmol/L, 0.666±0.123）. Their decreases were all significant （P〈0.05, P〈0.01, P〈0.01） in comparison to control group （without SP600125 treatment, 1.163±0.107）. In the other 3 groups pretreated with different concentrations of SB203580 （10 μmol/L, 1.507±0.099; 20 μmol/L, 1.698±0.107; 40 μmol/L, 1.857±0.054）, the expression of TIMMP-1 mRNA increased. Their levels were higher than those in the control group （without SB203580 treatment, 1.027 ± 0.061） with a significant statistical significance （P〈 0.01）. CONCLUSION： IL-1β has a direct action on hepatic fibrosis by up-regulating TIMMP-1 mRNA expression in ratessionin in rate HSC.JNK and p38 mitogen-activated protein kinases （MAPKs） are involved in IL-1β-induced TIMMP-1 gene expression, and play a distinct role in this process, indicating that p38 and .INK pathways cooperatively mediate TIMP-1 mRNA expression in rat HSC.

Activation of transcription factors NF-kappaB and AP-1 and their relations with apoptosis-associated proteins in hepatocellular carcinoma

AIM: To study the distribution pattern of transcription factors NF-kB and AP-1 and their relations with the expression of apoptosis associated-proteins Fas/FasL and ICH-1L/S in human hepatocellular carcinoma (HCC). METHODS: We performed in situ hybridization and immunohistochemical techniques for NF-kB, AP-1, Fas/FasL and ICH-1 in 40 cases of human HCC along with corresponding nontumoral tissues and 7 cases of normal liver tissues. RESULTS: Twenty-two (55%) and 25 (62.5%) of 40 cases for NF-κB and AP-1 were presented for nuclear or both nuclear and cytoplastic staining respectively, while less cases were presented for only cytoplastic staining for NF-κB (18%) and AP-1 (10%) in adjacent nontumoral tissues and negative staining in normal liver tissues. There was no statistically significant difference of NF-κB or AP-1 activation between well differentiated tumors and poorly differentiated tumors (P>0.05). NF-κkB activity is positively corresponded to AP-1 activation. The expression of ICH-1L/S was associated with the activation of NF-κB and AP-1 (P<0.05), but no significant relationship was found between Fas/FasL and NF-κB or AP-l(P>0.05). CONCLUSION: Activation of both NF-κB and AP-1 may be required for ICH-1L/S-induced apoptosis in HCC, but not for Fas/FasL-mediated apoptosis. NF-κB and AP-1 may play important roles in the pathogenesis of human HCC.

Associations between interleukin-1 polymorphisms and gastric cancers among three ethnicities

AIM:To investigate the associations between interleukin(IL)-1B and IL-1RN polymorphisms and gastric cancers among the Tibet,Hui and Han ethnicities.METHODS:Genomic DNA was extracted from peripheral blood of 210,205,and 202 healthy volunteers and from 155,158,and 197 gastric cancer patients from the Tibet,Hui,and Han populations,respectively.Polymorphisms in IL-1B and IL-1RN were analyzed by denaturing high-performance liquid chromatography.RESULTS:Carriers of the IL-1B-31 CC genotype had an increased risk of intestinal type gastric cancer [odds ratio(OR) = 2.17,P = 0.037] in the Tibet ethnicity.Carriers of the IL-1B 2/L genotype had an increased risk of both intestinal and diffuse types of gastric cancer(OR = 2.08,2.31,P = 0.007,0.016,respectively) in the Hui ethnicity.In the Han population,carriers of the IL-1B-31 CC,IL-1B-511CT,TT genotypes had increased risk of intestinal type gastric cancer(OR = 2.51,2.74,5.66,P = 0.005,0.002,0.000,respectively).CONCLUSION:IL-1B and IL-RN genotypes may differentially contribute to gastric cancer among the Tibet,Hui,and Han ethnicities in the Qinghai area of China.

Interleukin-1 and TNF-α polymorphisms and Helicobacter pylori in a Brazilian Amazon population

AIM： To study the association between Interleukin-1 （IL-1） and tumor necrosis factor （TNF）-α polymorphisms, 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-1β and TNF-α genes 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 IL- 1RN＊2 was more frequent among patients with gastric ulcers and adenocarcinoma. Carriers of the allele IL- RN＊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 gastricCONCLUSION： 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.

ANALYSIS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST GENE POLYMORPHISM IN CHINESE PATIENTS WITH ALZHEIMER'S DISEASE

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.

EFFECTS OF ACUMOXI ON IL2-IFN-NKC IMMUNOREGULATORY NETWORK AND ITS RELATED MACROPHAGE-IL1-Th NETWORK AND ON TUMOR——Observation on the Effect of Acumoxi on the Macrophage-IL1-Th Network and on the Metastasis of Hepatoma

Objective: To observe the effect of acumoxi (acupuncture and moxibustion) on macrophage (Mφ)-lL1-Th net-work and hydroperitoneum hepatoma (H 22) metastasis in mice. Methods: A total of 36 BALB/ c male mice bearing H 22 are randomly divided into control, acupuncture and acumoxi groups with 12 cases in each group. In the later 2 groups, Dazhui (GV 14) and Guanyuan (CV 4) are punctured once daily, continuously for 18 days, and in acumoxi group, the two acupoints were also moxibustioned alternatively with moxa stick once every day. After killing the mice, the tissue samples of the 3 groups are treated routinely step by step and analyzed by means of colorimetric analysis for determining the phagocytic function of the macrophages; and the content of IL1 of the Mφ supernatant is assayed with serum plate agglutination (SPA)-Ig floral hoop method of T helper cell (Th) monoclonal antibody; the weight of the reniportal lymph node, the kidney and the lung, and the number of the cancerous nodes on the pulmonary surface are calculated. Results: After acupuncture and moxibustion treatment, the immunoregulatory network indices of acumoxi group increase obviously compared with those of control group(P<0.01), showing an anti-metastasis effect of acumoxi on H 22. Conclusion: Results of the present study and those of our former research prove that acupuncture and moxibustion can suppress the tumor growth and H 22 metastasis by the enhancement of the immunoregulatory network.

Interleukin-1 receptor-associated kinase-2 is involved in IL-18-induced NF-κB activation

objective: To investigate whether interleukin-1 receptor-associated kinase-2 (IRAK-2) is involved in interleukin-18 (IL-18)-induced nuclear factor- κ B (NF-κ B) activation. Methods: Phosphorothioate oligodeoxynucleotide (ODN) was designed antisense to sequences of IRAK-2. Antisense IRAK-2 ODN was delivered by lipofectin encapsulation into cultured HepG2 cells. IRAK-2 mRNA expression was assayed by semiquantitative reverse transcription-PCR. The levels of NF- K B were measured by sandwich ELISA. Results: Antisense IRAK-2 ODN blocked IRAK -2expression. IL-18 activated NT- K B and the A value increased from a basal level of 0.115±0.004 to 2.141 ±0.038. Antisense IRAK-2 ODN inhibited IL-18-induced NT- K B activation in a dose (1-8μg )-dependent fashion. When the cells were treated with 4μg antisense IRAK-2 ODN for 8 h, a maximum inhibition of 45.4% was induced as shown by the reduction of the OD value from a control level of 2.141±0.038 down to 1.168±0.026. Conclusion: IRAK-2 can regulate IL-18-stimulated NF- K B activation.

AN EXPERIMENTAL STUDY OF THE INTERLEUKIN 1 LEVELS IN AQUEOUS HUMOR AFTER TRANSSCLERAL FIXATION OF INTRAOCULAR LENSES

Purpose. To study the interleukin 1 (IL-1)levels in aqueous humor after transscleral fixation of in- traocular lenses (IOLs) implantation in rabbits and discuss the effect of IL-1 on postoperative anterior ocular inflammation. Methods. Twenty-seven pigmented rabbits were divided into three groups: GI, transscleral fixation of posterior chamber (PC) IOLs implantation; G2, Lens of rabbits were removed without IOLs implanta- tion; G3, the control group, without surgical intervention. On the 1st, 3rd, 7th and 14th postoperative days, aqueous humor samples were obtained. Methyl thiazolyl tetrazolium (MTT) colormetry was used to detected for the presence of IL-1. The data were analyzed by using analysis of variance of SAS soft ware. Results’ It was found that IL-1 level in aqueous humor was increased after transscleral fixation of I- OLs implantation, IL-1 level reached its maximum on the 14th postoperative days in the IOL implanted group. IL-1 levels on 1st, 3rd, 7th and 14th days postoperatively was significantly higher (P<0. 05) in I- OLs implanted group than that of only extracapsular lenses extraction but no IOLs implantation group and that of the none surgical intervention group. COnclusions.IL-1 levels increased had a close relationship with a specific response to IOL implanta- tion. The increase of IL-1 may be suggested as the principal mediators of immunological and inflammatory responses, so that may play critical role in anterior ocular inflammative response after IOL implantation.

Serum inter-cellular adhesion molecule 1 is an early marker of diagnosis and prediction of severe acute pancreatitis

AIM:To determine if serum inter-cellular adhesion molecule 1(ICAM-1)is an early marker of the diagnosis and prediction of severe acute pancreatitis(SAP) within 24 h of onset of pain,and to compare the sensitivity,specificity and prognostic value of this test with those of acute physiology and chronic health evaluation(APACHE)Ⅱscore and interleukin-6(IL-6). METHODS:Patients with acute pancreatitis(AP)were divided into two groups according to the Ranson's criteria:mild acute pancreatitis(MAP)group and SAP group.Serum ICAM-1,APACHEⅡand IL-6 levels were detected in all the patients.The sensitivity,specificity and prognostic value of the ICAM-1,APACHEⅡscore and IL-6 were evaluated. RESULTS:The ICAM-1 level in 36 patients with SAP within 24 h of onset of pain was increased and was significantly higher than that in the 50 patients with MAP and the 15 healthy volunteers(P<0.01).The ICAM-1 level(25 ng/mL)was chosen as the optimum cutoff to distinguish SAP from MAP,and the sensitivity,specificity,positive predictive value,negative predictive value(NPV),positive likelihood ratio and negative likelihood ratio were 61.11%,71.42%,0.6111,0.7142, 2.1382 and 0.5445,respectively.The area under the curve demonstrated that the prognostic accuracy of ICAM-1(0.712)was similar to the APACHE-Ⅱscoring system(0.770)and superior to IL-6(0.508)in distinguishing SAP from MAP. CONCLUSION:ICAM-1 test is a simple,rapid and reliable method in clinical practice.It is an early marker of diagnosis and prediction of SAP within the first 24 h after onset of pain or on admission.As it has a relatively low NPV and does not allow it to be a stand-alone test for the diagnosis of AP,other conventional diagnostic tests are required.

Involvement of Shp-2 phosphatase in IL-1α mediated mouse embryo fi- broblast MMP-1 secretion and migration

Objective: To investigate the relation between Shp-2 (a cytoplasmic tyrosine phosphotase) and matrix metalloproteinase-1 (MMP-1) in the migration of mouse embryo fibroblast cell. Methods: Shp-2 -/-embryo fibroblast was separated from Shp-2 knockout mouse on E10. 5, and Shp-2 cDNA was transfected into Shp-2 -/- cell. The cell migration was observed with the wound healing, the MMP-1 expression and secretion was analyzed by immunoblotting and immunoprecipitation. The activation of MMP-1 in the supernatant was detected with type I collagenase activity assay after the stimulation of IL-1α compared with E10. 5 mouse embryo fibroblast cell(Shp-2 +/+). Results: There was obvious migration in Shp-2 +/+ cells and Shp-2 -/-R cells, but not in Shp-2 -/- cells. The shape of Shp-2 -/- cell was epithelial-like. The expression and secretion was increased in Shp-2 +/+ cells and Shp-2 -/-R cells, and it had not changed in Shp-2 -/- cell. The activation of MMP-1 was lower in Shp-2 -/- cells compared to the other cells. Conclusion: IL-1 induces the expression and secretion of MMP-1α at the physical dose, and the cell migration is involved in MMP-1 by way of Shp-2 signal transduction.

Modulation of cellular and humoral immune responses to anHIV-1 DNA vaccine by interleukin-12 and interleukin-18 DNA immunization

Objective: To investigate the effect of interleukin-12 (IL-12) and interleukin-18 (IL-18)DNA immunization on immune response induced by HIV-1 DNA vaccine and to explore new strategies for therapeutic HIV DNA vaccine. Methods: The recombinant expression vector pCI-neoGAG was constructed by inserting HIV Gag gene into the eukaryotic expression vector pCI-neo. Balb/c mice were immunized with pCI-neoGAG alone or co-immunized with the DNA encoding for IL-12 or IL-18.Anti-HIV antibody and IFN-γ were tested by ELISA,and splenocytes were isolated for detecting antigen-specific lymphoproliferative responses and specific CTL response by MTT assay and LDH assay respectively. Results: The anti-HIV antibody titers of mice co-immunized with pCI-neoGAG and the DNA encoding for IL-12 or IL-18 were lower than that of mice immunized with pCI-neoGAG alone(P<0.01). In contrast, the IFN-γ level of mice co-immunized with pCI-neoGAG and the DNA encoding for IL-12 or IL-18 was higher than that of mice immunized with pCI-neoGAG alone (P<0.01).Furthermore, compared with mice injected with pCI-neoGAG alone, the specific CTL cytotoxity activity and antigen-specific lymphoproliferative responses of mice immunized with pCI-neoGAG and the DNA encoding for IL-12 or IL-18 were significantly enhanced respectively (P<0.01). Conclusion: The DNA encoding for IL-12 or IL-18 together with HIV DNA vaccine may enhance specific Th-1 responses and cellular immune response elicited in mice. Hence, the DNA encoding for IL-12 or IL-18 are promising immune adjuvants for HIV-1 DNA vaccine.

体外培养肾小球系膜细胞CDK_2表达变化的实验研究

目的 探讨白细胞介素 1 (IL 1 )和白细胞介素 4 (IL 4 )对肾小球系膜细胞周期素依赖激酶 2 (CDK2 )表达的影响。方法 利用体外培养的大鼠肾小球系膜细胞 ,分别采用噻唑蓝掺入法、流式细胞仪检测、Westernblot等方法观察了IL 1促进系膜细胞增生前后CDK2 的表达变化 ,及同时应用IL 4后对上述表达变化的影响。结果 IL 1可以明显促进系膜细胞增生 ,同时观测到CDK2 表达增高 ;IL 4可以抑制IL 1诱导的系膜细胞增生 ,同时发现CDK2 表达减弱。结论 IL 1促进系膜细胞增生的同时CDK2 的表达明显增高 ,而同时应用IL 4后上述改变的程度均有所减弱 。

综合治疗联合人工肝治疗慢性重型肝炎的临床研究

目的 观察人工肝治疗慢性重型肝炎的临床疗效。方法 对60例慢性重型肝炎患者在综合治疗基础上给予人工肝治疗。结果 60例慢性重型肝炎患者治疗前血清胆红素[(656.7±297.8)μmol/L],内毒素[(60.2±11.3)ng/L]、肿瘤坏死因子α[(2835.9±810.7)ng/L]、白介素-1β[(2041.9±890.6)ng/L]、白介素-6[(162.5±178.6)ng/L]、凝血酶原活动度为22.2％±10.3％,均有明显的消化症状,经人工肝治疗后,血清胆红素、内毒素、肿瘤坏死因子α下降[(436.1±255.7)μmol/L,(30.8±10.6)ng/L,P<0.01;(2462.1±920.7)ng/L,P<0,05],但对白介素-1β[(2031.5±836.8)ng/L,P>0.05]及白介素-6[(141.7±154.7)ng/L,P>0.05]无明显下降。凝血酶原活动度上升[(38.1％±13.2％),P<0.01],部分患者消化道症状明显改善,人工肝治疗慢性重型肝炎治愈及好转率为38.3％,降低了慢性重型肝炎的病死率。结论 人工肝为重型肝炎的治疗提供了有效手段。

高速投射物压力波对肝脏细胞功能的间接作用

用高速投射物压力波在体外致伤大鼠,结果发现压力波可直接损伤大鼠组织器官,伤后大鼠巨噬细胞上清液中白介素—1(IL—1)活性明显升高,此上清液还可显著地抑制肝细胞蛋白合成功能。提示压力波对机体既有直接的力学损伤作用,又有间接的生物效应。压力波间接生物效应的原理可能与细胞因子等的分泌有关。