精神分裂症患者致炎性细胞因子和酪氨酸羟化酶mRNA表达水平的研究

目的探讨精神分裂症的外周神经免疫机制及其与临床症状的关系。方法检测精神分裂症患者致炎性细胞因子白介素-1β（IL-1β）、肿瘤坏死因子-α（TNF—α）以及酪氨酸羟化酶（TH）的mRNA表达水平，采用逆转录-聚合酶链反应及半定量检测技术，分别检测39例精神分裂症患者（患者组）、25例同胞（同胞组）及30名正常对照（对照组）外周血单个核细胞（PBMC）IL-1β、TNF-α及TH基因表达水平，同时应用阳性和阴性症状量表（PANSS）评定精神分裂症患者临床症状。结果患者组、同胞组及对照组IL-1β的mRNA表达水平分别为1．52±1．01、1．52±1．09和0．74±0．38；TNF—α的mRNA表达水平分别为1．18±0．99、1．01±0．87和0．70±0．29；TH的mRNA表达水平分别为0．55±0．33、0．61±0．32和0．28±0．20。患者组和同胞组的IL-1β、TNF—α、TH的mRNA表达水平均明显高于对照组（P〈0．05或P〈0．01）。患者组IL-1β（r=0．420）、TNF—α（r=0．430）的mRNA表达水平与PANSS的-般病理症状分呈正相关（P〈0．01）。同胞组与对照组合并统计，IL-1β与TNF-α的mRNA表达水平呈正相关（r=0．847，P〈0．01）；IL-1β与TH的mRNA表达水平呈正相关（r=0．666，P〈0．01）。患者组仅IL-1β与TNF—α的mRNA表达水平呈正相关（r=0．942，P〈0．01）。结论精神分裂症患者PBMC细胞TH、IL-1β和TNF—α的mRNA表达水平高于正常，且与精神分裂症的-般病理症状显著相关。     

休克期切痂对烫伤大鼠全身和肠道局部免疫功能的影响

目的　观察休克期切痂对烫伤大鼠全身和肠道局部免疫功能的影响 ,探讨其可能的机制。　方法　选用 96只Wistar大鼠。取其中 2 4只大鼠的躯干部皮肤冻存于液氮中 ,另取 8只作正常对照组。余下 6 4只造成 30 %TBSAⅢ度烫伤后 ,随机分为A组 2 4只 ,伤后不作任何处理 ;B组 2 4只 ,伤后 2 4h腹腔注射等渗盐水 5 0ml/kg,一次性切痂后用上述冻存异体皮覆盖 ;C组 1 6只 ,伤后 72h进行处理 ,方法同B组。检测A、B组大鼠伤后 2、4、8d和C组伤后 4、8d及正常对照组大鼠的脾淋巴细胞增殖功能、血浆和肠组织白细胞介素 (IL)2水平、肠黏液分泌型免疫球蛋白A(sIgA)及肠组织中二胺氧化酶 (DAO)含量的变化。　结果　各时相点下A、B、C组大鼠脾淋巴细胞增殖功能、血浆IL 2水平、肠组织IL 2及肠黏液sIgA含量均较正常对照组减少。B组伤后 4、8d和C组伤后 8d的脾淋巴细胞增殖功能接近正常对照组 ,血浆和肠组织IL 2水平明显高于A组 (P <0.0 1)。伤后 4、8d,B组肠黏液sIgA含量分别为 (3.5 1± 2 .1 4 )、(3.0 3± 0 .95 )mg/g,C组分别为 (1 .4 0± 0 .6 4 )、(1 .5 2± 1 .2 6 )mg/g,B组较C组增加近 1倍 (P 0.0 1 )。A组伤后 4、8d肠组织DAO活性低于正常对照组和B组 (P 0.0 5)。结论　休克期切痂有助于烫伤大鼠全身和肠道     

Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats

Peripheral and central injections of recombinant human interleukin-1β (IL-1β) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1β (4 μg/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 μg/rat, i.c.v.) abrogated the effects of centrally administered IL-1β (30 ngn/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 μg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1β (4 μg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1β on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms.     

Inhibition of tissue factor surface expression in human peripheral blood monocytes exposed to cytokines

Interleukin (IL)-4, IL-10, IL-13 and transforming growth factor beta (TGF-β) are known to regulate several monocyte functions, including inhibition of the synthesis of different cytokines. Using quantitative RT-PCR and flow cytometry analysis we investigated the effects of these cytokines on bacterial lipopolysaccharide (LPS)-induced tissue factor (TF) expression in human monocytes. The effects of IL-4 and IL-10 on monocyte chemoattractant protein-1 (MCP-1)- and C-reactive protein (CRP)-induced TF expression were also studied. A direct comparison revealed that IL-4, IL-10 and IL-13 all down-regulated LPS-induced TF expression in a concentration-dependent manner without the need for priming. In contrast, TGF-β required 4 h of priming to inhibit TF expression induced by LPS. IL-10 was the most powerful inhibitor, causing almost complete inhibition at 5 ng/ml. IL-4 and IL-13 exhibited a significantly lower inhibitory capacity even at concentrations of 100 ng/ml. IL-4 and IL-10 showed similar concentration-dependent inhibition of MCP-1- and CRP-induced TF expression. We also showed that the regulatory effect of the interleukins occurred at the mRNA level. In vivo , these inhibitory cytokines may play an important regulatory role in preventing thrombosis. IL-10, in particular, may be a possible candidate as a TF-preventing drug.     

Abdominal vagotomy attenuates interleukin-1β-induced nitric oxide release in the paraventricular nucleus region in conscious rats

Nitric oxide (NO) has recently been shown to modulate the hypothalamic–pituitary–adrenal axis response to interleukin-1β (IL-1β). We measured levels of nitrite (NO₂⁻) and nitrate (NO₃⁻) in the hypothalamic paraventricular nucleus (PVN) region using an in vivo brain microdialysis technique in conscious rats. Intraperitoneally administered IL-1β produced a significant increase in both NO₂⁻ and NO₃⁻ levels in the PVN region. We also examined the possible involvement of the abdominal vagal afferent nerves in this effect. In abdominal-vagotomized rats, the increase was significantly attenuated compared to that in sham-operated rats. Our results suggest that the abdominal vagal afferent nerves are involved in intraperitoneally administered IL-1β-induced NO release in the PVN region.     

商陆多糖Ⅰ对荷S180小鼠的抑癌,增强免疫和造血保护作用

商陆多糖Ⅰ(PEP Ⅰ)10,20mg·kg~1 ip能显著抑制S180生长,最大抑瘤率可达51.7％,Cy 10mg·kg~1 ip.抑瘤率为55.1％,两者合用抑瘤率为68.6％,PEP-Ⅰ治疗能显著促进脾脏增生,但不影响体重,PEP-Ⅰ治疗后,小鼠的T淋巴细胞转化及白介素2(IL-2)产生能力显著高于对照组,计数外周白细胞,骨髓有核细胞并用[~3H]TdR参入法观察rmGM-CSF刺激骨髓细胞增殖.结果表明PEP-Ⅰ与Cy合用治疗至d 11的外周白细胞数,骨髓有核细胞数和骨髓细胞的增殖能力显著高于单用Cy组,以上实验结果说明EPP-Ⅰ可能通过增强T淋巴细胞功能来抑制移植性肿瘤生长,并具有保护造血功能的作用。     

Regional brain kinetics of 6-fluoro-(β-11C)-L-dopa and (β-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography

Summary The regional brain kinetics of (-11C)-L-dopa and 6-fluoro-(-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 ± 0.0007 (S.D) and 0.0057 ± 0.0006 min1 for (-11C)-L-dopa and 6-fluoro-(-11C)-L-dopa, respectively. After pre-treatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 ± 0.0015 min-1) for (11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(-11C)L-dopa (0.0092 ± 0.0015 min–1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(-11C)-L-dopa significantly contributes to background radioactivity.     

Brain kinetics of 11 C-labelled L-tryptophan and 5-hydroxy-L-tryptophan in the Rhesus monkey

Summary 5-Hydroxy-L-tryptophan labelled with 11 C is introduced as a tracer for the in vivo assessment of brain serotonin synthesis in the Rhesus monkey using positron emission tomography, PET. Increasing radioactivities were seen in the striatal area in contrast to that seen in other brain regions. Following 11 C-labelled L-tryptophan an even spread of brain radioactivity was seen. This selective increase most probably results from the decarboxylation of tracer and retention of formed products since no striatal increase of radioactivity was seen when 5-hydroxy-L-tryptophan labelled with 11 C in the carboxy-position was administered. Furthermore, pretreatment of the monkey with a centrally active decarboxylase inhibitor (NSD 1015,10 mg/kg) did not lead to increased striatal radioactivities after the administration of 5-hydroxy-(-11C)-L-tryptophan. The selective utilization of the radiotracer in the striatal area increased with a rate constant calculated to be 0.0055 ± 0.0015 min^–1 (n = 5) using the surrounding brain as reference area. A non-significant influence of radiolabelled metabolites to the rate constants measured was shown after pretreatment of the monkeys with selective and non-selective monoamine oxidase inhibitors, respectively. These results may give a basis for the use of the new tracer 5-hydroxy-(-11 C)-L-tryptophan in PET-studies of brain serotonin metabolism in health and disease.     

Synergistic action of immunostimulatory DNA and fcgamma receptor IIB-crosslinking on B-cell phenotype and function

CpG DNA functions via the toll-like receptor-9 (TLR-9) receptor, inducing B cell proliferation and promoting immunoglobulin production. B cell responses to CpG DNA-containing immune complexes could be important in chronic autoimmunity and immune responses to bacterial components. Therefore, we investigated the potential synergy of CpG DNA-stimulation with FcgammaR clustering (CFR) on splenic B cell activity. CFR-induced splenocyte proliferation was significantly increased compared to treatment with CpG DNA alone. While the levels of interleukin-10 (IL-10) were increased in CpG DNA-treated splenocyte cultures, particularly following FcgammaRII/III-clustering, CFR treatment reduced IL-6 levels. B-cell maturation in culture was enhanced by CFR. Indeed, the frequency of IgG expressing cells after stimulation with CpG DNA was increased and was even higher after CFR stimulation. Furthermore, the frequency of plasma cell precursors was markedly increased by stimulation with CFR. Late splenic B cell subsets, transitional type 2 (T2) and mature (M) B cells, responded strongly to CpG DNA with proliferation and the response was enhanced by FcgammaR-clustering. Immature transitional type 1 (T1) B cells showed distinctly lower proliferative response to CpG DNA and very small effects of FcgammaR-clustering, despite similar expression of Fcgamma-receptors by all B cell subsets. In conclusion, these data show synergistic impact of CpG DNA and simultaneous FcgammaR-clustering on B cell proliferation and differentiation.