慢性盆腔炎患者促炎因子与抗炎因子的关系

目的:探讨慢性盆腔炎患者血清促炎因子与抗炎因子的表达与相关性。方法:选择87例慢性盆腔炎患者作为病例组,选择同期健康体检妇女69例作为对照组,ELISA法检测血清TNF-α、IL-1β、IL-6和抗炎细胞因子IL-4、IL-10的表达。结果:病例组患者血清TNF-α、IL-1β和IL-6表达高于对照组(P<0.05),而血清IL-4和IL-10表达低于对照组(P<0.05);病例组患者血清促炎因子的表达与抗炎因子的表达呈负相关(P<0.05)。结论:慢性盆腔炎患者促炎因子过度激活,而抗炎因子被抑制,并且二者表达具有一定的相关性,共同促进慢性盆腔炎的发生发展。     

Subacute cutaneous lupus erythematosus based on a study of 15 cases

15 cases of subacute cutaneous lupus erythematosus are reported. The diagnosis was based on the presence of the typical clinical features, on the histologic and immunpathologic examination of lesional skin and on the characteristic laboratory findings. 8 patients had annular type, 4 patients had papulosquamosus type of the characteristic skin signs of subacute cutaneous lupus erythematosus. In 3 patients both types of lesions existed simultaneously. 5 patients fulfilled the American Rheumatism Association criteria for systemic lupus erythematosus, however the systemic symptoms (arthritis, arthralgia, fever, myalgia, photosensitivity) were mild. 4 patients had positive ANA test, anti-Ro/SSA antibodies were determined in 5 patients, anti-RNP antibodies were detected in 8 patients. Anti-dsDNA antibodies were not detected. Subacute cutaneous lupus erythematosus is an intermediate subset in severity between discoid lupus erythematosus and severe systemic lupus erythematosus, therefore a milder form of therapy should be chosen.     

Zytokine in der Dermatologie

The skin is a target as well as a source of cytokines.Accordingly, the regulation of immune responses by cytokines is not limited to transient immune cells. It is rather a network of resident and transient immunocompetent cells which constitutively generate a relatively low amount of cytokines.Upon stimulation, various cutaneous cells such as keratinocytes, Langerhans cells, endothelial cells, fibroblasts,melanocytes or endothelial cells are able to synthesize large amounts of cytokines and to express cytokine receptors. A dysregulation and abnormal production of cytokines or cytokine receptors can be observed in several skin diseases.This knowledge may allow the development of new strategies to treat inflammtory allergic, as well as neoplastic skin diseases.Accordingly, cytokines such as interferons or cytokine antagonists such as anti TNF-α are already used for the treatment of certain inflammatory skin diseases and skin tumors.     

细胞因子抗体芯片在筛选NEC血清蛋白标记物中的应用价值

目的:应用细胞因子抗体芯片(cytokine antibodychip,CAC)分析新生儿坏死性小肠结肠炎(neonatal necrotiz-ing enterocolitis,NEC)患儿血清中炎性细胞因子表达的变化。方法:采用CAC技术平台测定6例NEC患儿(NEC组)和4例正常健康人(对照组)血清中79种细胞因子。按照至少在4个样本中信号值>400为表达有意义的细胞因子,筛选出有表达意义的细胞因子,应用芯片差异显著性分析(significance analysis of microarray,SAM)软件对有表达意义的细胞因子进行差异表达分析,初步获得NEC差异表达细胞因子。结果:筛选到白介素-8(IL-8),表皮生长因子(EGF),巨噬细胞炎性蛋白-1β(MIP-1β)和生长相关致癌基因(GRO)等4个在NEC患儿血清中低表达的细胞因子以及瘦素(Leptin)这一高表达细胞因子。聚类分析表明,上述5个差异表达的细胞因子能够明显区分NEC组和正常健康对照组。结论:CAC是一种高效、快速的蛋白质组学技术,利用CAC从血清中筛选NEC相关蛋白分子标记物是可行的。     

Genetics in patients with psoriatic arthritis

OBJECTIVES: HLA antigens were studied in 100 Hungarian patients suffered from psoriatic arthritis. Genetic markers for the development of different clinical pattern of the disease and skin disorder were identified. METHODS: Determination of class I and class II antigens was performed by using microlymphocytotoxicity assay. RESULTS: The frequency of HLA-Cw6, HLA-B16 (and its split B-39) and HLA-B27 antigens were significantly higher in psoriatic arthritis patients than in the Hungarian general population. No connection was found between HLA-DR4, DR7, B17 antigens and psoriatic arthritis. The patients were classified according to the subgroups proposed by Gladman. The comparisons between the clinical subgroups revealed a significant association of HLA-B27 with spondylitis (Gladman 4, 5, 6, 7). There was no association between HLA DR4 and polyarticular pattern of the disease (Gladman 3, 7). Psoriasis seemed to be significantly associated only with HLA-Cw6. There was a higher frequency of HLA-B38 in psoriatic arthritis patients with erythroderma.     

Local and systemic concentrations of tumour necrosis factor-alpha, interleukin-6 and interleukin-8 in bacterial osteomyelitis

Osteomyelitis is a major cause of morbidity worldwide but there are few data investigating pathogenesis of infection and no investigations into local secretion of proinflammatory cytokines in patients. Tumour necrosis factor-alpha (TNF), interleukin (IL)-6 and IL-8 concentrations were measured in pus of infected bone from 30 Zambian patients with chronic osteomyelitis (principally caused by Staphylococcus aureus), in plasma, and after lipopolysaccharide stimulation of whole-blood leucocytes. Patients had reduced body mass index compared to controls (P = 0.025) and an acute-phase response. Elevated concentrations of proinflammatory cytokines were detected in bone compared to plasma (all P < 0.0002). Bone IL-8 concentrations were greater than IL-8 levels after lipopolysaccharide stimulation of whole blood (P < 0.01). In contrast, systemic and ex-vivo-stimulated concentrations of proinflammatory cytokine were similar in patients and controls, despite differences in body mass index and an acute-phase response. In summary, we observed marked local TNF, IL-6 and IL-8 secretion in established bacterial osteomyelitis without systemic cytokine release.     

Cytokines and immunotherapy in infectious diseases

Cytokines are essential mediators in infection and inflammation. Almost all cytokines have not only positive but also noxious effects: the proinflammatory cytokines released during severe infections in high concentrations lead to organ damage and death. The antagonistic anti-inflammatory cytokines inhibit the defense against infections. Immunotherapy through modulation of the cytokine response may aim at inhibition of the proinflammatory and reinforcement of the anti-inflammatory cytokine response, so as to limit the damage of inflammation. In patients with sepsis this has so far been little successful, probably owing to the multiple effects of the cytokines. Inhibition of proinflammatory cytokines was successful, on the other hand, in patients with rheumatoid arthritis or Crohn's disease. Another possibility is to aim, on the contrary, at reinforcement of the proinflammatory and inhibition of the anti-inflammatory cytokine response, to strengthen the resistance of the host. This has given favourable results in a limited number of infections.     

Impact of the omega-3 to omega-6 polyunsaturated fatty acid ratio on cytokine release in human alveolar cells

Background: ω‐3 polyunsaturated fatty acids (PUFAs) and ω‐6 PUFAs have opposing influences on inflammation. The objective was to determine whether lipopolysaccharide (LPS)–induced cytokine release by human alveolar cells was affected by changes in the ω‐3/ω‐6 ratio of cell membranes induced by different supplies of PUFAs. Methods: After LPS challenge, PUFAs were added to alveolar cells as docosahexaenoic acid (DHA, ω‐3) and arachidonic acid (AA, ω‐6) in 4 different DHA/AA ratios (1:1, 1:2, 1:4, and 1:7), and the effects on cytokine release were measured. Results: The supply of 1:1 and 1:2 DHA/AA ratios reversed the baseline predominance of ω‐6 over ω‐3 in the ω‐3/ω‐6 PUFA ratio of cell membranes. The release of proinflammatory cytokines (tumor necrosis factor α, interleukin‐6, and interleukin‐8) was reduced by 1:1 and 1:2 DHA/AA ratios (P < .01 to P < .001) but increased by 1:4 and 1:7 DHA/AA ratios (P < .01 to P < .001) vs control. The 1:1 and 1:2 ratios increased the release of anti‐inflammatory interleukin‐10 (P < .001). The balance between proinflammatory and anti‐inflammatory cytokines showed an anti‐inflammatory response with 1:1 and 1:2 ratios and a proinflammatory response with 1:4 and 1:7 ratios (P < .001). Conclusions: This study showed that proinflammatory cytokine release was dependent on the proportion of ω‐3 in the ω‐3/ω‐6 ratio of alveolar cell membranes, being reduced with the supply of a high proportion of DHA and increased with a high proportion of AA, respectively. These results support the biochemical basis for current recommendations to shift the PUFA supply from ω‐6 to ω‐3 in nutrition support of patients with acute lung injury.     

Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial

BACKGROUND: Elevated circulating concentrations of proinflammatory cytokines may contribute to the pathogenesis of congestive heart failure (CHF). In vitro studies suggest that vitamin D suppresses proinflammatory cytokines and increases antiinflammatory cytokines. OBJECTIVE: We evaluated the effect of vitamin D supplementation on the survival rate and different biochemical variables in patients with CHF. DESIGN: One hundred twenty-three patients randomly received either 50 mug vitamin D(3)/d plus 500 mg Ca/d [D(+) group] or placebo plus 500 mg Ca/d [D(-) group] for 9 mo. Biochemical variables were assessed at baseline and after 9 mo. The survival rate was calculated for a follow-up period of 15 mo. RESULTS: Ninety-three patients completed the study. Significant treatment effects were observed on logarithmic-transformed serum concentrations of 25-hydroxyvitamin D (P = 0.001), parathyroid hormone (P = 0.007), tumor necrosis factor alpha (P = 0.006), and interleukin 10 (P = 0.042). 25-Hydroxyvitamin D increased by 26.8 ng/mL in the D(+) group but increased only by 3.6 ng/mL in the D(-) group. Compared with baseline, parathyroid hormone was significantly lower and the antiinflammatory cytokine interleukin 10 was significantly higher in the D(+) group after 9 mo. The proinflammatory cytokine tumor necrosis factor alpha increased in the D(-) group but remained constant in the D(+) group. The survival rate did not differ significantly between the study groups during the follow-up period. CONCLUSIONS: Vitamin D(3) reduces the inflammatory milieu in CHF patients and might serve as a new antiinflammatory agent for the future treatment of the disease. Our data provide evidence for the involvement of an impaired vitamin D-parathyroid hormone axis in the progression of CHF.     

Proinflammatory cytokine expression by Theileria annulata infected cell lines correlates with the pathology they cause in vivo

Control of Theileria annulata is currently best achieved by the use of live attenuated cell line vaccines. However, the mechanisms underlying attenuation are unclear and there is a need to rapidly produce new cell line vaccines, which could safely and effectively vaccinate cattle against tropical theileriosis. There is increasing evidence to suggest that proinflammatory cytokines produced by T. annulata infected cells play a central role in both pathology and immune evasion. This study aimed to test this hypothesis and to evaluate cytokine expression as a marker of virulence. The pathogenicity and protective efficacy of cloned T. annulata cell lines that expressed different levels of proinflammatory cytokines were compared. In two independent trials using different stocks of T. annulata, cell lines that expressed higher levels of proinflammatory cytokines induced severe reactions, and in some cases death, when used to vaccinate groups of cattle. In contrast, low cytokine expressing lines induced low post-vaccinal reactions. The results clearly demonstrated that cytokine expression by T. annulata infected cells could be used as a marker of virulence and provided strong evidence to support a role for cytokines in the induction of pathology. Both high and low cytokine expressing cell lines protected cattle against heterologous challenge infection, offering the possibility of using cytokine expression to rapidly select new safe, potent vaccines against tropical theileriosis without the need for culture attenuation.     

Acute alcohol intake impairs lung inflammation by changing pro- and anti-inflammatory mediator balance.

Previous studies have shown that alcohol (ethanol [EtOH]) intoxication impairs lung immunity by affecting cytokines pivotal to the inflammatory process. The objective of this study was to test the hypothesis that acute alcohol intoxication impairs lung innate immunity by downregulating the expression of proinflammatory mediators while simultaneously upregulating anti-inflammatory mediators. EtOH was administered to the mice 0.5h prior to an intratracheal injection of Escherichia coli lipopolysaccharide (LPS). The animals were killed either 4 or 24h after LPS to recover plasma, lungs, and bronchoalveolar lavage fluid. Lung inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), IL-6, macrophage inhibitory factor (MIF), IL-10, TGF-beta, and receptors for TNF-alpha, IL-1beta, IL-6, and TGF-beta as well as glycoprotein (gp)130 and corticosterone (CS) levels were evaluated at mRNA and protein level. While the mRNA expression and the soluble TNF-Rp55 levels were significantly upregulated by EtOH, LPS-induced TNF-alpha activity, TNF-Rp55 mRNA expression, and soluble TNF-Rp55 levels were significantly suppressed. The LPS-induced expression of IL-1beta, IL-6, MIF, gp130, and receptors IL-1RI, IL-1RII, and IL-6Ralpha were also significantly impaired by EtOH. EtOH increased significantly the basal IL-10 activity at 3h, which continued to remain elevated even at 24h. The EtOH effect on IL-10 activity persisted even in LPS-challenged mice. EtOH and LPS augmented lung CS levels independently of each other. EtOH suppressed upregulation of TGF-beta1 mRNA expression by LPS and blocked completely LPS-induced TGF-beta1 secretion. In conclusion, the data suggest that the suppression of acute lung inflammation by EtOH intoxication is largely due to impairment by EtOH of proinflammatory cytokine signaling at the levels of cytokine expression and secretion as well as receptor expression and soluble receptor activity. The augmentation by EtOH of anti-inflammatory mediators' secretion most likely shifts the cytokine balance in the anti-inflammatory direction.     

Phytosterols Synergize With Endotoxin to Augment Inflammation in Kupffer Cells but Alone Have Limited Direct Effect on Hepatocytes

Introduction: Phytosterols are implicated in the development of parenteral nutrition–associated liver disease. A newly proposed mechanism for phytosterol‐mediated parenteral nutrition–associated liver disease is through phytosterol‐facilitated hepatic proinflammatory cytokine release following exposure to intestinally derived bacteria. Whether the proinflammatory effects are liver cell specific is not known. Aim: To determine if phytosterols cause inflammation in hepatocytes or Kupffer cells independently or require costimulation by lipopolysaccharide (LPS). Methods: In an in vivo study, neonatal piglets on parenteral nutrition for 11 days received an 8‐hour infusion of LPS. In the in vitro studies, neonatal piglet Kupffer cells and hepatocytes were treated with media, media + 1% soy oil, or media + 1% soy oil + 100µM phytosterols. After 24‐hour incubation, cells were treated with farnesoid X receptor (FXR) agonist obeticholic acid or liver X receptor (LXR) agonist GW3965 and challenged with LPS or interleukin 1β. Results: LPS administration in piglets led to transient increases in proinflammatory cytokines and suppression of the transporters bile salt export pump and ATP‐binding cassette transporter G5. In hepatocytes, phytosterols did not activate inflammation. Phytosterol treatment alone did not activate inflammation in Kupffer cells but, combined with LPS, synergistically increased interleukin 1β production. FXR and LXR agonists increased transporter expression in hepatocytes. GW3965 suppressed proinflammatory cytokine production in Kupffer cells, but obeticholic acid did not. Conclusions: LPS suppresses transporters that control bile acid and phytosterol clearance. Phytosterols alone do not cause inflammatory response. However, with costimulation by LPS, phytosterols synergistically maximize the inflammatory response in Kupffer cells.     

Homocysteine at pathophysiologic concentrations activates human monocyte and induces cytokine expression and inhibits macrophage migration inhibitory factor expression

OBJECTIVE: Homocystinemia is an important independent risk factor for atherosclerosis. Inflammatory cytokines play key roles in the development of atherogenesis. This study investigated the effect of homocysteine on inflammatory cytokine expression. METHODS: Human monocytes were treated in vitro with a variety of DL-homocysteine concentrations that ranged from physiologic concentration to higher than pathophysiologic concentration, and we analyzed their expressions of inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-8, interleukin-12, and migration inhibitory factor. RESULTS: DL-homocysteine at a marginal physiologic concentration of 2 microg/mL (15 microM) activated monocytes. In addition, DL-homocysteine at the pathophysiologic dose of 25 microg/mL (185 microM) induced mRNA and protein expressions of inflammatory cytokines tumor necrosis factor-alpha, IL-1beta, interleukin-6, interleukin-8, and interleukin-12. Moreover, at the larger dose of 50 microg/mL (370 microM) DL-homocysteine decreased expression of migration inhibitory factor at the mRNA and protein levels. CONCLUSION: These findings suggest that homocysteine may contribute to the initiation and progression of vascular disease by activating monocytes, resulting in the secretion of cytokines that amplify the inflammatory response.     

Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus?

Acetylcholine, the principal vagus neurotransmitter, inhibits inflammation by suppressing the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic acetylcholine receptor subunit (alpha7nAChR) that explains why vagus nerve stimulation is anti-inflammatory in nature. Strong expression of alpha7nAChR in the synovium of rheumatoid arthritis and psoriatic arthritis patients was detected. Peripheral macrophages and synovial fibroblasts respond in vitro to specific alpha7nAChR cholinergic stimulation with potent inhibition of proinflammatory cytokines. Fibroblasts balance inflammatory mechanisms and arthritis development through feedback cholinergic stimulation by nearby immune cells. Collagen induced arthritis in alpha7nAChR^(-/-) mice was significantly severe and showed increased synovial inflammation and joint destruction compared to the wild-type mice. Similar to vagal nerve stimulation and alpha7nAChR agonists, polyunsaturated fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also suppress inflammation. In view of their similar anti-inflammatory actions, it is proposed that vagal nerve stimulation, alpha7nAChR agonists and EPA and DHA may augment the formation of anti-inflammatory lipid molecules: lipoxins, resolvins, protectins and maresins. This implies that therapies directed at regulation of the cholinergic and alpha7nAChR mediated mechanisms and enhancing the formation of lipoxins, resolvins, protectins and maresins may halt and/or ameliorate rheumatoid arthritis, lupus and other rheumatological conditions.     

Dietary fish oil increases tumor necrosis factor secretion but decreases interleukin-10 secretion by murine peritoneal macrophages

Dietary fish oil has immunomodulatory effects that are mediated in part by its effects on cytokines. Secretion of the inflammatory and the anti-inflammatory cytokines tumor necrosis factor (TNF) and interleukin (IL)-10 by murine resident peritoneal macrophages was monitored after ex vivo stimulation with lipopolysaccharide. Macrophages were obtained from mice fed a corn oil diet containing 200 g/kg corn oil or a fish oil diet containing 180 g/kg fish oil and 20 g/kg corn oil. Dietary fish oil increased secretion of the proinflammatory cytokine, TNF, but decreased secretion of the anti-inflammatory cytokine, IL-10. The cytokines appeared in the medium after 1.5 h and peaked at 6-12 h. Neutralizing antibodies against TNF and IL-10 had little effect on secretion of the other cytokine, indicating that the effects of fish oil on TNF and IL-10 secretion by these cells are independent of one another. Furthermore, although inhibiting prostaglandin production enhanced TNF secretion by macrophages from mice fed the corn oil diet, it did not affect IL-10 secretion by macrophages in this group. Blocking leukotriene B(4) production also did not affect IL-10 secretion in macrophages from mice fed a nonpurified diet. These results demonstrate that fish oil has an overall pro-inflammatory effect given its effects on secretion of both inflammatory and anti-inflammatory cytokines by resident peritoneal macrophages.     

Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects

Intermittent fasting and caloric restriction have been shown to extend life expectancy and reduce inflammation and cancer promotion in animal models. It was hypothesized that intermittent prolonged fasting practiced during the month of Ramadan (RIF) could positively affect the inflammatory state. To investigate this hypothesis, a cross-sectional study was designed to investigate the impact of RIF on selected inflammatory cytokines and immune biomarkers in healthy subjects. Fifty (21 men and 29 women) healthy volunteers who practiced Ramadan fasting were recruited for the investigation of circulating proinflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor α), immune cells (total leukocytes, monocytes, granulocytes, and lymphocytes), and anthropometric and dietary assessments. The investigations were conducted 1 week before Ramadan fasting, at the end of the third week of Ramadan, and 1 month after the cessation of Ramadan month. The proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α; systolic and diastolic blood pressures; body weight; and body fat percentage were significantly lower (P < .05) during Ramadan as compared with before Ramadan or after the cessation of Ramadan fasting. Immune cells significantly decreased during Ramadan but still remained within the reference ranges. These results indicate that RIF attenuates inflammatory status of the body by suppressing proinflammatory cytokine expression and decreasing body fat and circulating levels of leukocytes.     

BBI抑制LPS诱导的肠道上皮细胞炎性因子的表达

目的探讨大豆来源的胰蛋白酶抑制剂(BBI)对LPS诱导的肠道上皮细胞炎性因子表达的抑制作用及其机制。方法用MTT法检测LPS和BBI对肠道上皮细胞的毒性作用。先用BBI预处理肠道上皮细胞,再用LPS刺激,采用实时荧光定量PCR检测细胞内炎性因子(TNF-α、IL-1β、IL-8和MCP-1)的表达,通过NF-κB-luc荧光素酶质粒和蛋白质印迹法(Western Blot)检测NF-κB的活性。结果 LPS最大浓度(10 000 ng/mL)和BBI最大浓度(1 000μg/mL)对细胞均无毒性作用。LPS处理可显著地上调肠道上皮细胞炎性因子(TNF-α、IL-1β、IL-8和MCP-1)的表达,其上调作用和LPS的浓度成正相关;LPS处理肠道上皮细胞3 h后炎性因子表达最高,随时间延长有所下降;LPS对肠道上皮细胞炎性因子的上调作用具有剂量和时间效应;BBI预处理肠道上皮细胞6 h时,BBI对LPS诱导肠道上皮细胞炎性因子表达的抑制作用最明显,且具有剂量效应。结论通过对肠道上皮细胞内NF-κB的抑制,BBI能够显著地抑制LPS诱导炎症因子的表达。