A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice

The predisposition of nonobese diabetic (NOD) mice to develop autoimmunity reflects deficiencies in both peripheral and central tolerance. Several defects have been described in these mice, among which aberrant antigen-presenting cell function and peroxynitrite formation. Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-gamma. This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism. Here, we provide evidence that IFN-gamma fails to induce tolerizing properties in dendritic cells from highly susceptible female mice early in prediabetes. This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production. However, the use of a peroxynitrite inhibitor can rescue tryptophan catabolism and tolerance in those mice. This is the first report of an experimental autoimmune disease in which defective tolerance is causally linked to impaired tryptophan catabolism.     

Transgenic expression of decoy receptor 3 protects islets from spontaneous and chemical-induced autoimmune destruction in nonobese diabetic mice

Decoy receptor 3 (DCR3) halts both Fas ligand- and LIGHT-induced cell deaths, which are required for pancreatic beta cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in beta cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants.     

当归多糖对乙肝病毒转基因小鼠树突状细胞功能状态的影响

目的:探讨当归多糖对乙肝病毒转基因小鼠树突状细胞功能状态的影响。方法:取当归多糖处理和未处理的转基因小鼠脾脏来源的单个核细胞,以重组小鼠粒细胞-巨噬细胞集落刺激因子和重组小鼠白细胞介素-4培养诱导树突状细胞,显微镜下观察其形态,流式细胞仪检测其表面共刺激分子(CD80,CD86),MTT法检测其刺激同种异体淋巴细胞增殖的能力,ELISA法测定培养上清液中IL-12、r-IFN水平等方法进行研究。结果:当归多糖处理组小鼠树突状细胞的表面协同刺激分子(CD86)表达水平、刺激同种异体淋巴细胞增殖能力和细胞因子产生水平均高于对照组(P<0.05)。结论:当归多糖可以促进乙肝病毒转基因小鼠树突状细胞的成熟,上调其表面协同刺激分子CD86的表达,增强了其促淋巴细胞细胞增殖和分泌IL-12、r-IFN的能力,加强其抗原递呈能力,诱导细胞免疫反应,在乙肝病毒转基因小鼠抗病毒免疫中可能发挥一定的作用。     

系统性红斑狼疮患者外周血淋巴细胞CD28/CTLA-4分子表达的研究

目的探讨系统性红斑狼疮(systemic lupus erythematosus,SLE)患者外周血淋巴细胞CD28/CTLA-4分子和CD28/CTLA-4mRNA的表达。方法研究对象为SLE患者49例(活跃期30例、缓解期19例)及对照组23例。外周血单个核细胞(peripheral blood mononuclear cell,PBMCs)经梯度密度离心法分离后分佛波醇乙酯(PMA)(10ng/ml)及伊屋诺霉素(500ng/ml)刺激组和不加刺激剂组两组培养。将PBMCs分别培养24、48、72及96小时。应用流式细胞计量术(flow cytometry,FCM)检测外周血淋巴细胞培养前后CD28及CTLA-4分子的表达。采用RT-PCR方法检测CD28mRNA和CTLA-4mRNA的表达。结果刺激前后SLE患者CD3+及CD8+T细胞上CD28分子表达量与对照组比较差异均无统计学意义(P>0.05)。刺激前活跃期SLE患者CD3+T细胞上CTLA-4分子表达量较对照组明显降低[(0.78±0.51)%vs(1.34±0.76)%,P<0.05]。刺激后72小时SLE患者CD3+T细胞及CD8+T细胞上CTLA-4分子表达量仍低于对照组,但差异无统计学意义(P>0.05)。刺激前后PBMCs中CD28mRNA及CTLA-4mRNA表达情况与刺激前后CD3+T细胞上CD28及CTLA-4分子变化情况相似。刺激前SLE患者CD3+T细胞上CTLA-4分子表达量与SLE活动指数(SLEDAI)呈显著的直线负相关关系(P<0.001)。结论 SLE患者T细胞CTLA-4分子存在表达及上调机制障碍,提示CD28分子及CTLA-4分子存在功能失衡,这种失衡可能通过一定的机制参与SLE的发病过程。     

Neonatal tumor necrosis factor alpha promotes diabetes in nonobese diabetic mice by CD154-independent antigen presentation to CD8(+) T cells

Neonatal islet-specific expression of tumor necrosis factor (TNF)-alpha in nonobese diabetic mice promotes diabetes by provoking islet-infiltrating antigen-presenting cells to present islet peptides to autoreactive T cells. Here we show that TNF-alpha promotes autoaggression of both effector CD4(+) and CD8(+) T cells. Whereas CD8(+) T cells are critical for diabetes progression, CD4(+) T cells play a lesser role. TNF-alpha-mediated diabetes development was not dependent on CD154-CD40 signals or activated CD4(+) T cells. Instead, it appears that TNF-alpha can promote cross-presentation of islet antigen to CD8(+) T cells using a unique CD40-CD154-independent pathway. These data provide new insights into the mechanisms by which inflammatory stimuli can bypass CD154-CD40 immune regulatory signals and cause activation of autoreactive T cells.     

Pretreatment with melatonin protects against cyclophosphamide‐induced oxidative stress and renal damage in mice

Cyclophosphamide (CP) is widely used in treatment of different cancers. Nephrotoxicity is one of the dose‐limiting side effects of CP. This study was carried out to investigate the effect of melatonin (MEL) on CP‐induced nephrotoxicity in mice. In this study, 50 Swiss albino mice (20–25 g) were randomly divided into five groups. Mice were pretreated with MEL intraperitoneally (i.p) in doses of 5, 10 and 20 mg/kg for five consecutive days, and CP (200 mg/kg, i.p) was administrated on the 5th day 1 h after the last dose of MEL. Then on day 6, blood samples were collected to determine serum creatinine (Cr) and blood urea nitrogen (BUN) levels. The kidneys were used for histological examination, biochemical assays and real‐time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) level, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activity were assessed in renal tissue. In addition, the expression of SOD2 and PGx1 was measured using real‐time PCR method in renal tissue. Results showed that CP administration significantly increases Cr, BUN, MDA, PC, NO level and MPO activity. It also decreases renal GSH level, SOD, GPx and CAT activity. Pretreatment with MEL (especially 20 mg/kg, i.p.) for 5 days prevented these changes; however, it did not affect the SOD activity. Our results revealed that MEL might be useful for prevention of the nephrotoxicity induced by CP through ameliorative effects on biochemical indices and oxidative stress parameters.     

Garcinol protects against cerebral ischemia-reperfusion injury in vivo and in vitro by inhibiting inflammation and oxidative stress

Garcinol, a polyisoprenylated benzophenone derivative, is isolated from fruit rind of Garcinia indica. It is known to exert potent anti-inflammatory and anti-oxidative properties. In the present study, we tried to investigate the neuroprotective effects of garcinol on a rat model with middle cerebral artery occlusion/reperfusion (MCAO/R) and a cell model subjected to oxygen glucose deprivation and reperfusion (OGD/R). In vivo, we found that the rats with garcinol treatment showed a lower neurological deficit score and a smaller infarct size compared with the rats with ischemia-reperfusion (I/R) injury alone. We further found that garcinol treatment decreased cerebral I/R-induced inflammatory cytokines and oxidative stress, including inhibiting the production of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), decreasing the levels of malonaldehyde (MDA) and nitric oxide (NO), and suppressing the decreased superoxide dismutase (SOD) activity. Moreover, the suppression of toll-like receptor (TLR) 4 and nuclear NF-κB (p65) expression by garcinol was found both in vivo and in vitro. In addition, NF-κB activator or TLR4 overexpression was employed to investigate its involvement in the effects of garcinol. The results showed that NF-κB activator or TLR4 overexpression at least in part reversed the anti-inflammatory and anti-oxidative properties of garcinol in vitro. Taken together, the data suggest that garcinol could protect against cerebral I/R injury through attenuating inflammation and oxidative stress, and improving neurological function. The molecular mechanism might be related to its suppression of TLR4/NF-ĸB signal pathway.     

妊娠期高血压疾病患者外周血单个核细胞及胎盘晚期糖基化终末产物受体表达及与氧化应激的关系

目的 探讨外周血单个核细胞(PBMCs)及胎盘晚期糖基化终末产物受体(RAGE)表达及其与氧化应激的关系,了解其在妊娠期高血压疾病发生、发展中的作用.方法 同期收治的轻、中度妊娠期高血压疾病患者15例,重度妊娠期高血压疾病患者15例,正常晚期妊娠20例,抽取肘静脉血及留取胎盘,用蛋白质免疫印迹法(Western blot)测定PBMCs及胎盘RAGE蛋白的表达,并测定血浆及胎盘丙二醛(MDA)水平及超氧化物歧化酶(SOD)活性.结果 妊高征患者血浆及胎盘MDA水平高于正常晚期妊娠组,且重度妊娠期高血压疾病患者较轻、中度妊娠期高血压疾病患者升高(P均＜0.01);轻、中度妊娠期高血压疾病组血浆及胎盘SOD活性低于正常晚期妊娠组(血浆P＜0.01,胎盘P＜0.05),在重度妊娠期高血压疾病组血浆及胎盘SOD活性进一步降低,低于轻、中度妊娠期高血压疾病组(血浆P ＜0.05,胎盘P＜0.01);RAGE蛋白在正常晚期妊娠组、轻、中度妊娠期高血压疾病组和重度妊娠期高血压疾病组胎盘中的表达量分别为0.305±0.045、0.439±0.047、0.975±0.057,在PBMCs中的表达量分别为0.301±0.067、0.399±0.062、0.572±0.089,RAGE蛋白在轻、中度妊娠期高血压疾病组胎盘和PBMCs中的表达高于正常晚期妊娠组(P均＜0.01),在重度妊娠期高血压疾病组中的表达高于正常晚期妊娠组及轻、中度妊娠期高血压疾病组(P均＜0.01);PBMCs内RAGE蛋白表达与血浆MDA水平呈中度正相关(轻、中度妊娠期高血压疾病组:r=0.46,P ＜0.05;重度妊娠期高血压疾病组;r=0.47,P＜0.05);胎盘RAGE蛋白表达与胎盘MDA水平呈高度正相关(轻、中度妊娠期高血压疾病组:r=0.82,P＜0.01;重度妊娠期高血压疾病组:r=0.88,P＜0.01).结论 PBMCs及胎盘RAGE表达与氧化应激相互关联,共同在妊高征的发病机制中发挥了重要作用.     

A defect in interleukin 12-induced activation and interferon gamma secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes mellitus.

The function of natural killer T (NKT) cells in the immune system has yet to be determined. There is some evidence that their defect is associated with autoimmunity, but it is still unclear how they play a role in regulating the pathogenesis of T cell-mediated autoimmune diseases. It was originally proposed that NKT cells could control autoimmunity by shifting the cytokine profile of autoimmune T cells toward a protective T helper 2 cell (Th2) type. However, it is now clear that the major function of NKT cells in the immune system is not related to their interleukin (IL)-4 secretion. In fact, NKT cells mainly secrete interferon (IFN)-gamma and, activated in the presence of IL-12, acquire a strong inflammatory phenotype and cytotoxic function.     

间充质干细胞与人脐血CD34+细胞共移植对NOD/SCID小鼠造血重建的影响

目的 观察间充质干细胞(MSC)与不同比例脐血CD34+细胞共移植对NOD/SCID小鼠造血重建的影响,明确MSC与脐血CD34+细胞共移植的最适数量.方法 给60Coγ射线照射的雌性NOD/SCID小鼠共移植人MSC和不同比例的脐血CD34+细胞,观察共移植后42 d内小鼠外周血白细胞和血小板变化,并于移植后42 d处死小鼠,用流式细胞术检测外周血、骨髓和脾脏人源细胞含量.结果 与单纯脐血CD34+细胞移植相比较:①脐血CD34+细胞与1、5和10倍数量的MSC共移植时,可明显减轻外周血白细胞和皿小板的下降幅度(P<0.01),提前1周使白细胞和血小板恢复至正常水平(P<0.05),三组间差异无统计学意义(P>0.05);②MSC与不同比例的脐血CD34+细胞共移植均可明显提高外周血、骨髓和脾脏造血细胞植入率.比例为10:1时,外周血、骨髓和脾脏中的人源细胞(huCD45+细胞)含量分别增加了(2.8±0.6)倍、(3.5±0.9)倍和(5.2±0.6)倍,增加倍数差异均有统计学意义(P<0.01),达到了最佳的植入效果.结论 脐血CD34+细胞与10倍数量的MSC共移植可达到最佳的促进造血重建作用.     

HBsAg致敏自体树突细胞联合阿德福韦和单用阿德福韦对CHB者IFN-γ和IL-4的影响比较

目的 观察乙型肝炎表面抗原致敏的自体树突细胞联合阿德福韦酯(联合组)与单用阿德福韦(阿德福韦组)治疗前后慢性乙型肝炎(CHB)患者外周血干扰素γ(IFN-γ)和白细胞介素4(IL-4)的变化,对照观察其抗乙型肝炎病毒的免疫效应.方法 用实时荧光聚合酶链反应法检测治疗前,治疗后4、12、24及48周末患者血清乙型肝炎病毒脱氧核糖核酸(HBV DNA).利用双抗体夹心酶联免疫吸附测定法检测相应时间点的血清中IFN-γ和IL-4水平.结果 CHB患者丙氨酸转氨酶和天冬氨酸转氨酶治疗后两组间改善值基本相同;HBV DNA改善值联合组从治疗12周末起明显高于阿德福韦组(P＜0.05),在治疗48周末两组改善值基本相同.联合组IFN-γ水平在24周达到高峰,联合组在12、24周末明显高于阿德福韦组(P＜0.05),阿德福韦组IL-4在12、24周末较治疗前下降(P＜0.05).结论 两种治疗均能使机体免疫部分恢复或增强,联合组有明显优势,这种作用可能是随着治疗后病毒载量下降和CD4+T淋巴细胞活性的重建而出现的.     

CTLA-4 blockade induces tumor pyroptosis via CD8+ T cells in head and neck squamous cell carcinoma

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肝脏间质树突状细胞在多器官功能障碍综合征中的变化与意义

目的探讨肝脏间质树突状细胞在多器官功能障碍综合征（MODS）免疫紊乱机制中的影响与作用。方法150只C57BL／6小鼠经腹腔注射酵母多糖复制MODS模型，随机分为正常对照组和致伤后3～6h、12～48h、5～7d及10～12d组。观察各组小鼠肝脏间质树突状细胞的形态学变化及其表面标记物CD11c、CD205、CD80和I—A^B的表达水平；用流式细胞术检测各组外周血CD4^＋与CD8^＋的T细胞数量及CD4’／CD8’比值。结果急性损伤期（12～48h）肝脏间质树突状细胞大量增生，CD11c、CD205、CD80和I—A^b表达均较正常对照组显著上升（P均〈0．01），外周血T细胞CD4^＋／CD8^＋比值则明显下降（P〈O．01）；功能衰竭期（10～12d）肝脏间质树突状细胞继续增生，但CD205、CD80和I—A^b表达较急性损伤期显著减少（P〈0．05或P〈0．01），外周血T细胞CD4^-／CD8^＋比值下降至最低。结论肝脏间质树突状细胞参与并影响了MODS中肝脏局部与全身免疫失衡及免疫抑制过程。     

NOD鼠体内CD_4~+NKG2D~+T细胞与CD_8~+T细胞间关系

目的探讨NOD鼠体内CD_4~+NKG2D~+T细胞与CD_8~+T细胞间关系。方法动态监测NOD鼠外周血中CD_4~+NKG2D~+T及CD8+NKG2D~+T细胞在不同周龄频率。利用IGRP206-214特异性CTL清除的NOD鼠,对其外周血中CD_4~+NKG2D+/CD_4~+T及CD8+NKG2D+/CD_8~+T细胞频率进行分析。将磁珠分选所得CD_4~+NKG2D~+T细胞分别与经CFSE标记的纯CD_4~+NKG2D-T细胞、CD_8~+T细胞共培养4 d,检测体系中CD_4~+NKG2D-T细胞、CD_8~+T细胞CFSE的荧光强度变化。结果 NOD鼠外周血CD_4~+NKG2D+/CD_4~+T及CD8+NKG2D+/CD_8~+T细胞频率均随其1型糖尿病疾病进程发展逐渐升高,且二者之间呈正相关。IGRP206-214特异性CTL清除的NOD鼠,外周血中CD_4~+NKG2D+/CD_4~+T细胞频率随CD8+NKG2D+/CD_8~+T细胞频率降低显著下降。与单独培养的CD_4~+NKG2D-T细胞相比,加入CD_4~+NKG2D~+T细胞的培养体系中,CD_4~+NKG2D-T细胞增殖加快。但CD_4~+NKG2D~+T细胞对CD_8~+T增殖作用不明显。结论 NOD鼠体内存在着一群与1型糖尿病疾病进程正相关的CD_4~+NKG2D~+T细胞,且该群细胞极有可能是通过直接作用于CD_4~+NKG2D-T细胞而间接对CD_8~+T细胞产生作用。     

致敏小鼠CD4~+ CD25~+调节性T细胞磁珠分选及体外扩增

本研究探讨致敏小鼠CD4+ CD25+调节性T细胞的分选及体外扩增。流式细胞术检测致敏小鼠及正常小鼠体内CD4+ CD25+ Treg细胞水平,免疫磁珠分选方法从小鼠脾细胞中分选出CD4+T细胞、CD4+ CD25+ Treg细胞和CD4+ CD25-T细胞,负载抗CD3/CD28单克隆抗体MACSiBead联合IL-2共同刺激CD4+ CD25+ Treg细胞进行体外扩增培养,用0.4%台盼蓝染色并计数检测细胞的活性,流式细胞术检测分选后细胞纯度、主要表面标记及Foxp3基因的表达。结果表明:致敏小鼠体内CD4+ CD25+ Treg水平较正常小鼠升高(P<0.05)。分选出CD4+ CD25+ Treg细胞纯度平均达到87%,细胞活性大于97%,高表达Foxp3基因。体外扩增2周后细胞数扩增倍数能够达到42倍,CD4+ CD25+ Treg细胞所占比例为85.32%,Foxp3表达由(76.92±1.72)%稍下降至(75.33±2.11)%(P>0.05)。结论:免疫磁珠分选法能够分选出高纯度的CD4+ CD25+ Treg细胞,该分选方法不影响分选靶细胞的细胞活力;体外成功扩增了CD4+ CD25+ Treg细胞,扩增后的CD4+ CD25+ Treg细胞表面标记及Foxp3基因表达无明显改变。     

Red wine protects diabetic patients from meal-induced oxidative stress and thrombosis activation: a pleasant approach to the prevention of cardiovascular disease in diabetes

BACKGROUND: Oxidative stress and thrombosis have been reported to be increased in diabetic patients and involved in the pathogenesis of cardiovascular complications. It has been demonstrated in diabetic patients that consumption of a meal is accompanied by the generation of an oxidative stress and of a hypercoagulable state. It is well recognized that red wine shows antithrombotic activity and that its ingestion increases plasma antioxidant capacity in man. In this study the possibility that red wine consumption may reduce the oxidative stress and thrombosis produced postprandially in diabetic patients has been evaluated. SUBJECTS AND METHODS: Twenty type 2 diabetic patients were studied during fasting consumption of 300 mL of red wine, or during a meal accompanied, or not, by red wine ingestion. RESULTS: Plasma glucose, insulin, triglycerides, total plasma radical-trapping capacity, activated factor VII and prothrombin fragments 1 + 2 were measured in basal state and at 60, 120 and 180 min after the start of each experiment. Low-density lipoprotein (LDL) oxidation was also evaluated at baseline and after 120 min Plasma glucose, insulin, triglycerides and LDL oxidation significantly increased, while the total plasma radical-trapping parameter significantly decreased during the meal test. Consumption of red wine in the fasting state significantly increased total plasma radical-trapping parameter activity, while wine ingestion with a meal counterbalanced the decrease of total plasma radical-trapping parameter and the increase of LDL oxidation. Meal consumption induced an increase in plasma prothrombin fragments 1 + 2 and activated factor VII in diabetic patients. Wine ingestion with the meal significantly reduced the production of both prothrombin fragments 1 + 2 and activated factor VII. Fasting consumption of red wine alone did not show effects on coagulation or LDL oxidation. CONCLUSION: This finding confirms that in the absorptive phase free radicals are produced in diabetic patients, which reduce serum antioxidant defences, increase LDL oxidation and activate the coagulation system. Red wine consumption during a meal significantly preserves plasma antioxidant defences and reduces both LDL oxidation and thrombotic activation. The consumption of a moderate amount of red wine during meals may have a beneficial effect in the prevention of cardiovascular disease in diabetic patients.     

Apple pectin: A natural source for cancer suppression in 4T1 breast cancer cells in vitro and express p53 in mouse bearing 4T1 cancer tumors,in vivo

PurposeIncrease in the number of cancer related deaths has made the study on developing new drugs and treatments essential. One of the main aims in developing new therapies is to use natural resources which have the ability to induce apoptosis. Pectin is one of these natural compounds, a complex polysaccharide found in apples with anti-cancer properties. The aim of this study was to examine anti-cancer properties of pectic acid both in vitro in 4T1 breast cancer cells and in vivo using an animal model of breast cancer.Experimental designMTT cell proliferation assays, double fluorescence staining (acridine orange/ethidium bromide) and cell cycle analysis were employed to measure apoptosis in vitro. 4T1 cells were implanted into female BALB/c mice for in vivo studies. Then tumor volumes, histological analysis and immunohistochemical staining of P53 and tunnel test were applied to evaluate apoptosis in tumors.ResultsThe results of in vitro studies showed that concentration of 0.1% of pectic acid could induce apoptosis, inhibit cell growth (p < 0.001) and reduce cell attachment, fragmented chromatin, and membrane blebbing as well as blocking the sub-G1 phase (p < 0.001). In addition, in vivo studies showed that pectic acid could inhibit the progression of tumors through over-expression of P53 and increasing the number of apoptotic cells.ConclusionOur results demonstrated that pectic acid, a natural component of apple, can prevent metastasis in both cancer cell lines and primary tumors. This potential effect is mainly due to its ability to induce apoptosis.     

Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice.

Development of effectors from naive CD4 cells occurs in two stages. The early stage involves activation and limited proliferation in response to T cell receptor (TCR) stimulation by antigen and costimulatory antigen presenting cells, whereas the later stage involves proliferation and differentiation in response to growth factors. Using a TCR-transgenic (Tg(+)) model, we have examined the effect of aging on effector generation and studied the ability of gamma(c) signaling cytokines to reverse this effect. Our results indicate that responding naive CD4 cells from aged mice, compared with cells from young mice, make less interleukin (IL)-2, expand poorly between days 3 to 5, and give rise to fewer effectors with a less activated phenotype and reduced ability to produce cytokines. When exogenous IL-2 or other gamma(c) signaling cytokines are added during effector generation, the Tg(+) cells from both young and aged mice proliferate vigorously. However, IL-4, IL-7, and IL-15 all fail to restore efficient effector production. Only effectors from aged mice generated in the presence of IL-2 are able to produce IL-2 in amounts equivalent to those produced by effectors generated from young mice, suggesting that the effect of aging on IL-2 production is reversible only in the presence of exogenous IL-2.     

Effect of intestinal microflora on the production of interleukin 10 and prostaglandin e(2) in serum and kupffer cells from germfree and conventional mice

To determine why germfree (GF) mice are less productivity of proinflammatory cytokines than conventional (CV) mice, we studied serum levels of interleukin 10 (IL-10) and prostaglandin E(2) (PGE(2)) in mice after treatment with lipopolyssacharide (LPS). A single injection of LPS caused an elevation of IL-10 in serum from GF, LPS-GF (germfree mice given drinking water containing LPS) and CV mice. The response was highest in serum from GF mice, and was lower in serum from LPS-GF mice compared with GF mice. Before LPS injection, serum PGE(2) was significantly higher in CV and LPS-GF mice than in GF ones. After LPS injection, a higher level of PGE(2) was maintained over 12 h in CV mice after LPS injection, while the LPS treatment reduced the level in LPS-GF mice and increased the level in GF mice. The levels of IL-10 in culture medium from Kupffer cells treated with LPS showed similar results to serum in GF and CV mice. These results suggest that high levels of IL-10 in serum from germfree mice may be partly responsible for the lower in vivo responsiveness of these proinflammatory cytokines to LPS in these mice, although PGE(2) was not responsible for the lower responsiveness of these inflammatory cytokines to LPS.