动脉粥样硬化小鼠主动脉组织中CXCL16和MMP-1表达

目的 探讨动脉粥样硬化小鼠主动脉组织中CXC型趋化因子配体16(CXCL16)和MMP-1的表达.方法 选取8周龄的SPF级ApoE基因敲除(ApoE-/-)雄性小鼠10只,给予高脂饲料喂养构建动脉粥样硬化模型(实验组),另选取8周龄的SPF级雄性小鼠10只给予普通饲料喂养作为对照组.两组小鼠均在喂养8周后处死,将心脏-主动脉整条分离.采用Western blot法检测两组小鼠主动脉组织中CXCL16和M M P-1蛋白表达.采用RT-PCR法检测主动脉组织中CXCL16和MMP-1 mRNA表达.结果 实验组小鼠主动脉组织CXCL16和MMP-1蛋白表达量高于对照组(P<0.05).实验组小鼠主动脉组织CXCL16和MMP-1 mRNA表达量高于对照组(P<0.05).结论 动脉粥样硬化小鼠主动脉组织中高表达炎症因子CXCL16和MMP-1.     

急性脑出血患者外周血CXCL12、TSP-1、D-D动态变化及与病情进展、近期预后的关系

目的 研究急性脑出血(ACH)患者血清CXC趋化因子配体12(CXCL12)、血小板反应蛋白-1(TSP-1)及D-二聚体(D-D)的动态变化及与疾病进展、近期预后的关系.方法 选取我院2018年1月—2019年10月收治的84例ACH作为研究组,按格拉斯哥昏迷评分量表(GCS)评分分为轻度亚组、中度亚组、重度亚组;又...     

CXCL16、 CD36 与颈动脉易损斑块并发脑梗死的关系

目的 探讨血清巨噬细胞趋化因子配体 16 （CXCL16） 及 CD36 水平与颈动脉粥样硬化易损斑块并发大动脉粥样硬化（LAA）性脑梗死的关系。方法 选取颈动脉粥样硬化易损斑块合并 LAA 性脑梗死的患者（脑梗组） 50 例、 有颈动脉粥样硬化易损斑块者（斑块组） 50 例; 同期健康体检者（对照组） 50 例。各组均接受颈动脉彩超检查。计算各组体质指数 （BMI）, 同时检测各组三酰甘油 （TG）、 总胆固醇 （TC）、 低密度脂蛋白胆固醇 （LDL-C）、 高密度脂蛋白胆固醇 （HDL-C）、 空腹血糖 （FBG）, 应用酶联免疫吸附试验 （ELISA） 测定各组血清 CXCL16 及 CD36 水平。Logistic 回归分析颈动脉粥样硬化易损斑块发生 LAA 性脑梗死的影响因素。结果 斑块组和脑梗组 BMI、 TG、 TC、 LDL-C、 FBG 水平高于对照组, HDL-C 水平低于对照组; 脑梗组 TG、 TC、 LDL-C、 FBG 水平高于斑块组, BMI、 HDL-C 水平低于斑块组（P＜0.05）。对照组、 斑块组及脑梗组的 CXCL16 和 CD36 水平均呈依次升高趋势（P＜0.05）。多因素 Logistic 回归分析显示, 高 TG、 LDL-C、 FBG、 CXCL16 及 CD36 是颈动脉粥样硬化易损斑块合并 LAA 性脑梗死的危险因素。结论 血清 CXCL16、 CD36 水平可作为颈动脉易损斑块的生物标志物; 联合检测血清 CXCL16、 CD36 水平有助于预测 LAA 性脑梗死。     

血清CXCL9和SFRP1在AECOPD合并肺栓塞患者中的表达及对预后的影响

目的 探讨血清CXC趋化因子配体9(CXCL9)和分泌型卷曲相关蛋白1(SFRP1)在慢性阻塞性肺疾病急性加重期(AECOPD)合并肺栓塞(PE)患者中的表达水平及其对预后的预测价值。方法 56例AECOPD合并PE患者为病例组，并收集同期的80例单纯AECOPD患者为对照组。采用酶联免疫吸附试验检测各组血清CXCL9、SFRP1水平。采用Logistic回归模型分析AECOPD发生PE的影响因素，绘制受试者工作特征(ROC)曲线评估血清CXCL9、SFRP1对AECOPD患者PE的预测价值，采用COX比例风险回归模型分析血清CXCL9、SFRP1对不良预后的影响。结果 与对照组比较，病例组AECOPD病程较长，血清CXCL9、SFRP1水平升高(P<0.05)。较长AECOPD病程(OR=1.420,95%CI:1.246～1.620)和较高CXCL9(OR=1.835,95%CI:1.502～2.241)、SFRP1(OR=1.608,95%CI:1.351～1.914)水平是AECOPD患者发生PE的独立危险因素。血清CXCL9、SFRP1均可预测AECOPD患者PE发生风...     

胍丁胺鞘内注射对骨癌痛大鼠痛行为及脊髓CXCL13表达的影响

目的 探讨胍丁胺鞘内注射对骨癌痛大鼠痛行为及脊髓趋化因子CXC配体13（CXCL13）表达的影响。方法 成年雌性SD大鼠60只,体质量200~220 g,采用随机数字表法分为3组：假手术组（A组）、骨癌痛组（B组）、骨癌痛+胍丁胺组（C组）,各20只。B、C组采用大鼠胫骨上端骨髓腔内注入Walker 256癌细胞的方法建立骨癌痛模型,A组胫骨髓腔内注射等量生理盐水,B、C两组鞘内置管。造模成功后,C组鞘内注射胍丁胺160 mg/kg,连续6天;B组鞘内给予等量生理盐水,连续6天;A组不作处理。于造模后第12天用von Frey丝测定3组大鼠机械缩足反射阈值（MWT）;痛阈测定结束后,麻醉处死大鼠,取脊髓组织,采用免疫荧光法检测CXCL13在神经元中的表达;采用Western blot法分析CXCL13蛋白表达及逆转录-聚合酶链反应（RT-PCR）法检测CXCLl3 mRNA的表达。结果 建模后12天,与A组比较,B、C组大鼠MWT明显低于A组,与B组比较,C组MWT高于B组,差异均有统计学意义（P<0.05）。建模后12天,与A组比较,B、C组大鼠CXCL13在脊髓背角神经元中表达增加,CXCL13蛋白及其mRNA表达明显增加（P<0.05）;与B组比较,C组大鼠CXCL13在脊髓背角神经元中表达降低,CXCL13蛋白及其mRNA表达明显减少（P<0.05）。结论 鞘内注射胍丁胺可有效改善大鼠骨癌痛痛觉过敏行为,其机制可能与抑制大鼠脊髓CXCL13表达有关。     

风湿性二尖瓣狭窄瓣膜组织CCL19和CCR7的表达

目的研究趋化因子配体19(CCL19)及其受体趋化因子受体7(CCR7)在风湿性二尖瓣狭窄(RMS)患者瓣膜组织中的表达、分布特点和细胞定位。方法采用GeneChip Human Gene1.0ST基因芯片和免疫组织化学染色法检测RMS病变二尖瓣瓣膜(A组,16例)和正常瓣膜(B组,3例)中CCL19和CCR7的表达情况。结果 A组CCL19和CCR7均高表达;其中,CCL19主要分布在炎症细胞区域,CCR7主要在瓣膜间质细胞表达。而B组中CCL19和CCR7均无明显表达。结论 RMS患者二尖瓣瓣膜组织中CCL19主要表达于浸润的炎症细胞,CCR7表达于瓣膜间质细胞,两者相互作用参与瓣膜的病理过程。     

CXC趋化因子及其受体与肺纤维化的研究进展

肺纤维化（pulmonary fibrosis,PF）是一种常见的、持续发展的、无法逆转的、致命的慢性肺部疾病,诊断后的中位生存期为2～4年,其特征是肺部细胞外基质沉积过多和瘢痕,导致功能衰竭、严重呼吸问题甚至死亡。大量研究表明,CXC趋化因子及其受体在肺纤维化和其他纤维增生紊乱的疾病中发挥重要作用。多项研究显示,CXC趋化因子可能成为许多疾病治疗的新靶点。本文主要对关键CXC趋化因子及其受体在肺纤维化中的作用作一综述,以期为肺纤维化的治疗提供参考。     

IL-17 CCL2 CXCL10在良性前列腺增生合并组织学炎症患者组织中的表达研究

目的探讨不同组织学炎症程度良性前列腺增生(BPH)患者前列腺组织中白细胞介素(IL)-17及其相关趋化因子的表达,为BPH组织学炎症机制提供依据。方法收集80例行尿道前列腺电切术(TURP)的BPH患者术中前列腺组织标本,根据组织病理学特征是否合并组织学炎症(HP)分为单纯组和炎症组。其中单纯组20例;炎症组分为合并轻度、中度、重度组织学炎症程度的BPH组织。采用免疫组织化学法检测前列腺增生组织IL-17蛋白,实时荧光定量聚合酶链反应(PCR)方法检测前列腺增生组织中CCL2、CXCL10mRNA。结果180例TURP切除的前列腺组织标本中,有60例(75%)患者前列腺组织中存在组织学炎症;2单纯组样本中IL-17表达很低;3IL-17蛋白其随炎症分级升高而升高(P<0.05);4合并重度组织学炎症的BPH组织中CCL2mRNA的表达明显高于非炎症组,上升为3倍,CXCL10则上升10倍(P<0.05)。结论 IL-17及趋化因子CCL2、CXCL10在合并前列腺炎的前列腺增生组织中表达高,可能在前列腺增生的组织学炎症中起重要作用。     

Association of CCL11, CCL24 and CCL26 with primary biliary cholangitis

BackgroundCCL11, CCL24 and CCL26 are potent chemokines for eosinophils. Since there has been no study reporting the association serum CCL11, CCL24 and CCL26 with fibrotic progression of PBC, the aim of this study is to explore the association.MethodsOne hundred and eight PBC patients, 52 patients with chronic hepatitis B (CHB) and 50 healthy controls (HC) were recruited. The sera were detected for CCL11, CCL24 and CCL26 using multiplex immunoassay. Other laboratory indicators were routinely measured. PBC was divided into four stages according to Scheuer's classification.ResultsSerum CCL11, CCL24 and CCL26 levels were significantly higher in PBC patients than those with CHB and HC (P < 0.05). The ROC analyses showed that all of the three CCLs performed well for identification of PBC (all P< or =0.001). The multiple linear regression analysis showed an independent relationship of CCL26 with APRI and FIB-4 in PBC patients, but no relationship of CCL11 and CCL24 with fibrotic indicators. Additionally, serum CCL11 and CCL26 were negatively correlated with histological stage of PBC, while serum CCL24 showed no statistical correlation.ConclusionSerum CCL11, CCL24 and CCL26 are upregulated in PBC. CCL11 and CCL26 are associated with fibrotic progression of PBC, but CCL24 is not.     

Synergistic induction of CCL5, CXCL9 and CXCL10 by IFN-γ and NLRs ligands on human fibroblast-like synoviocytes—A potential immunopathological mechanism for joint inflammation in rheumatoid arthritis

Interferon-γ (IFN-γ) is traditionally regarded as a proinflammatory cytokine by virtue of its strong macrophage activating potential and its association with Th1 driven immune responses. NOD1 and NOD2 are cytoplasmic receptors that can initiate the initial immune response by sensing bacterial components or danger signals. In this study, we investigated the immunopathological roles of IFN-γ and NOD1, 2 ligands iE-DAP/MDP on the activation of fibroblast-like synoviocytes (FLS) in RA. FLS constitutively express functional NOD1 and NOD2, and the gene and protein expression of NOD1 and NOD2 could be enhanced by the treatment with IFN-γ. The synergistic effect was observed in the combined treatment of IFN-γ and NOD1 ligand iE-DAP or NOD2 ligand MDP on the release of CCL5, CXCL9 and CXCL10 from FLS, and its effect was in a dose-dependent manner. The co-stimulation which IFN-γ combined with iE-DAP/MDP could abolish the inhibition of CXCL8 level by IFN-γ alone. Further investigations showed that synergistic effects on the production of CCL5, CXCL9 and CXCL10 in FLS stimulated by IFN-γ and iE-DAP/MDP were differentially regulated by intracellular activation of NF-κB, p38MAPK and ERK pathways. In conclusion, our data confirmed the inflammatory effect of IFN-γ and iE-DAP/MDP on human FLS for the first time and therefore provided a new insight into the IFN-γ combined with NOD1 or NOD2 activated immunopathological mechanisms mediated by distinct intracellular signal transduction in joint inflammation of RA.     

Suppressive effects of antimycotics on tumor necrosis factor-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes

Antimycotic agents are reported to improve cutaneous symptoms of atopic dermatitis or psoriasis vulgaris. Keratinocytes in these lesions excessively produce chemokines, CCL27, CCL2, or CCL5 which trigger inflammatory infiltrates. Tumor necrosis factor-alpha (TNF-alpha) induces production of these chemokines via activating nuclear factor-kappaB (NF-kappaB). We examined in vitro effects of antimycotics on TNF-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Antimycotics ketoconazole and terbinafine hydrochloride suppressed TNF-alpha-induced CCL27, CCL2, and CCL5 secretion and mRNA expression in keratinocytes in parallel to the inhibition of NF-kappaB activity while fluconazole was ineffective. Anti-prostaglandin E2 (PGE2) antiserum or antisense oligonucleotides against PGE2 receptor EP2 or EP3 abrogated inhibitory effects of ketoconazole and terbinafine hydrochloride on TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production, indicating the involvement of endogenous PGE2 in the inhibitory effects. Prostaglandin H2, a precursor of PGE2 can be converted to thromboxane A2. Ketoconazole, terbinafine hydrochloride and thromboxane A2 synthase (EC 5.3.99.5) inhibitor, carboxyheptyl imidazole increased PGE2 release from keratinocytes and reduced that of thromboxane B2, a stable metabolite of thromboxane A2. Carboxyheptyl imidazole also suppressed TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production. These results suggest that ketoconazole and terbinafine hydrochloride may suppress TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production by increasing PGE2 release from keratinocytes. These antimycotics may suppress thromboxane A2 synthesis and redirect the conversion of PGH2 toward PGE2. These antimycotics may alleviate inflammatory infiltration in atopic dermatitis or psoriasis vulgaris by suppressing chemokine production.     

High serum levels of CXC (CXCL10) and CC (CCL2) chemokines in untreated essential hypertension

Hypertension has been suggested to exert pro-inflammatory actions through increased expression of several mediators, including chemokines. Chemokines are involved in inflammatory and autoimmune disorders, and in the formation of atherosclerotic lesions through promotion of inflammatory cell migration. The aim of this study is to evaluate the influence of high blood pressure on circulating levels of the prototype chemokines C-X-C motif ligand (CXCL)10 and C-C motif ligand (CCL)2 in 140 patients with essential hypertension not affected by thyroid disorders or overt autoimmune or inflammatory diseases, and 140 gender- and age-matched healthy controls. Mean CXCL10 and CCL2 levels were significantly higher in hypertensive patients than in controls. Among hypertensive patients, chemokines levels were higher in those with systo-diastolic hypertension compared to those with isolated systolic hypertension. In a multiple linear regression model using CXCL10 or CCL2 as dependent variables and age, body mass index, glycemia, serum creatinine, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, triglycerides, and systolic or diastolic blood pressure values as covariates, only systolic or diastolic blood pressure values were significantly related to CXCL10 or CCL2 levels. In conclusion, this study demonstrates increased circulating levels of the prototype chemokines CXCL10 and CCL2 in patients with hypertension.     

Comparison of a novel CXCL12/CCL5 dependent migration assay with CXCL8 secretion and CD86 expression for distinguishing sensitizers from non-sensitizers using MUTZ-3 Langerhans cells

As the induction of contact hypersensitivity is the result of a series of cellular processes, including maturation and migration of epidermal dendritic cells (Langerhans cells (LC)), a battery of assays based on these in vivo events might provide a robust in vitro predictability model for distinguishing sensitizers from non-sensitizers. Therefore, assays with read-out for changes in CD86 expression and CXCL8 secretion were compared with a novel functional assay based on the in vitro migratory behaviour of LC. In all three assays LC derived from the human myeloid-leukaemia-cell-line MUTZ-3 (MUTZ-LC) were used. Exposure of MUTZ-LC to a panel of five sensitizers and three non-sensitizers resulted in increased CD86 expression in only 3/5 sensitizers, but also in 1/3 non-sensitizers. In contrast, CXCL8 secretion was uniformly increased after exposure to all sensitizers, but not after exposure to non-sensitizers. In a transwell migration assay, preferential migration of sensitizer-exposed MUTZ-LC towards CXCL12 was observed (5/5 sensitizers), whereas non-sensitizer-exposed MUTZ-LC only migrated towards CCL5 (3/3 non-sensitizers). In conclusion, the novel MUTZ-LC migration assay and analysis of CXCL8 secretion proved to be more successful than analysis of CD86 in predicting sensitizers from non-sensitizers and therefore warrant further investigation in the field of in vitro assay development.     

Bothrops moojeni venom and BmooLAAO-I downmodulate CXCL8/IL-8 and CCL2/MCP-1 production and oxidative burst response,and upregulate CD11b expression in human neutrophils

Bothrops snake venoms contain biologically active components, including L-amino acid oxidases (LAAO) that induce significant leukocyte accumulation at inflammatory sites characterized by early neutrophil infiltration. As it remains unclear how snake venoms modulate neutrophil activation and chemokine production, here we examined whether Bothrops moojeni crude venom (BmV) and its LAAO (BmooLAAO-I) affect expression of the surface activation markers CD11b and CD66b, production of the chemokines CCL2/MCP-1, CCL5/RANTES, CXCL8/IL-8, CXCL9/MIG, and CXCL-10/IP-10, and activation of oxidative burst in human neutrophils. Cell viability, expression of activation markers, and chemokine production were assessed by flow cytometry, while the oxidative burst response was measured by chemiluminescence. BmV at 50 and 75 µg/mL reduced CXCL8/IL-8 (p < 0.001 and p < 0.01, respectively) and CCL2/MCP-1 production (p < 0.05), while BmooLAAO-I at the same concentrations reduced only CCL2/MCP-1 production (p < 0.01). These effects were accompanied by CD11b upregulation (p < 0.05 for 50 and 75 µg/mL BmV; p < 0.01 for 50 and 75 µg/mL BmooLAAO-I) and CD66b downregulation (p < 0.05 for 50 and 75 µg/mL BmV). Both BmV and BmooLAAO-I at concentrations ranging from 0.625 to 5 µg/mL suppressed the oxidative burst of neutrophils stimulated with phorbol 12-myristate 13-acetate, while BmooLAAO-I at 2.5 and 5 µg/mL also suppressed the neutrophil response stimulated with opsonized zymosan. Considering that neutrophils participate in the pathogenesis of autoimmune and inflammatory diseases, the findings reported herein indicate that BmV and BmooLAAO-I are potential immunomodulating agents.     

IL-10 enhances CCL2 release and chemotaxis induced by CCL16 in human monocytes

CCL16 is a CC chemokine originally identified as a liver-expressed chemokine. Its expression has been detected in activated monocytes where it is up-regulated by stimulation with IL-10. This is in contrast with IL-10's inhibition of the expression of most chemokines. CCL16 is chemotactic for monocytes, lymphocyte and dendritic cells. We investigated whether CCL16 displays biological activities other than chemotaxis and whether IL-10 affects monocyte response to CCL16. We show that CCL16 induces the expression of CCL2 at the mRNA and protein level, but does not affect that of CCL5, CCL18 and proinflammatory cytokines. This effect was prevented by treatment with pertussis toxin and may thus be mediated by G-protein-coupled receptors. IL-10 markedly increased CCL2 production induced by CCL16, but suppressed that of CXCL8. It also enhanced the chemotactic response to CCL16. Addition of antibodies blocking CCR1, but not CCR8, prevented this enhanced chemotactic response and suggested that CCR1 is primarily involved. We propose that IL-10 modulates the effects of CCL16 on monocytes by increasing their CCR1-dependent response. The coordinated secretion of CCL16 and IL-10 may thus enhance monocyte infiltration.     

CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization

Chemokines are key players in the attraction and activation of leukocytes and are thus implicated in the recruitment of immune cells at sites of infection and/or inflammation. They exert their action by binding to seven-transmembrane G protein-coupled receptors. The chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 represents the single natural ligand for the chemokine receptor CXCR4. CXCL12 possesses angiogenic properties and is involved in the outgrowth and metastasis of CXCR4-expressing tumors and in certain inflammatory autoimmune disorders, such as rheumatoid arthritis. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor (VEGF). CXCR4 also acts as a co-receptor for entry of human immunodeficiency virus (HIV) in CD4(+) T cells. Finally, CXCL12/CXCR4 interactions were shown to play an important role in the migration of hematopoietic stem cells and their progenitors from, and their retention within, the bone marrow, a site characterized by high CXCL12 expression. As such, CXCR4 inhibitors may be utilized to inhibit HIV-1 infection, tumor growth and metastasis and to mobilize hematopoietic stem cells from the bone marrow in the circulation, where they can be collected for autologous stem cell transplantation. Here, we discuss the different aspects of CXCL12/CXCR4 biology as well as the development and anti-cancer/stem cell mobilizing activity of CXCR4 antagonists.     

CXCL10与CXCL12基因多态性与肺结核易感性的关系

目的 探讨趋化因子 CXCL10-135G/A 和 CXCL12-801G/A 的基因多态性与肺结核病易感性之间的关系。方法 应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术对 102 例结核病患者（病例组）和 115 例健康对照者（对照组）的 CXCL10-135G/A 和 CXCL12-801G/A 多态性进行基因分型,分析这两个位点多态性与结核病发生是否相关。结果 病例组和对照组 CXCL10-135G/A 与 CXCL12-801G/A 基因型分布符合 Hardy-Weinberg 平衡定律。CXCL10-135G/A 多态性基因型及等位基因的分布频率在病例组及对照组中差异均有统计学意义（均 P＜ 0.05）,病例组 G 等位基因的分布频率高于对照组,A 等位基因的分布频率低于对照组。CXCL12-801G/A 多态性基因型及等位基因的分布频率在病例组及对照组中差异均无统计学意义（均 P＞0.05）。结论 趋化因子 CXCL10-135G/A 基因多态性与肺结核易感性有关,而 CXCL12-801G/A 基因多态性与肺结核感染可能无关。