Nifedipine inhibits tumor necrosis factor-alpha-induced leukocyte adhesion to endothelial cells by suppressing vascular cell adhesion molecule-1 (VCAM-1) expression

We have previously shown that nifedipine, one of the most popular dihydropyridine-based calcium antagonists (DHPs), blocked tumor necrosis factor-alpha (TNF-alpha)-induced reactive oxygen species generation and subsequent monocyte chemoattractant protein-1 expression in endothelial cells (ECs), thus suggesting that nifedipine may inhibit monocyte recruitment, an initiating step in atherosclerosis. However, the effect of nifedipine on leukocyte adhesion to ECs, another pivotal step in the early stage of atherosclerosis, remains to be elucidated. In this study, we investigated whether nifedipine could inhibit TNF-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) expression and subsequent leukocyte adhesion to human umbilical vein endothelial cells (HUVEC). Nifedipine significantly inhibited TNF-alpha-induced up-regulation of VCAM-1 mRNA levels in HUVEC. Furthermore, nifedipine was found to block MOLT-3 (a human lymphoblastic cell line) cell adhesion to TNF-alpha-exposed HUVEC. The results suggest that nifedipine could inhibit TNF-alpha-induced leukocyte adhesion to ECs by suppressing VCAM-1 expression. Our present study provides a novel beneficial aspect of nifedipine on atherogenesis.     

Targeting intercellular adhesion molecule-1 (ICAM-1) to reduce rhinovirus-induced acute exacerbations in chronic respiratory diseases

Inflammopharmacology - The chronic respiratory non-communicable diseases, asthma and chronic obstructive pulmonary disease (COPD) are among the leading causes of global mortality and morbidity....     

Ginsenoside Rb1 inhibits tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human endothelial cells

We investigated whether ginsenoside Rb1 (Rb1) could block tumor necrosis factor-alpha (TNF-alpha)-induced over-expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and human lung microvascular endothelial cells (HMVECs-L). Cells were treated with various concentrations of TNF-alpha with or without Rb1 pre-treatment for 16 h. The mRNA and protein levels of VCAM-1 were determined with real-time polymerase chain reaction (PCR) and flow cytometry, respectively. Human monocytic THP-1 cells labeled with fluorescent dye (Calcein-AM) was used for the adhesion assay on HUVEC monolayers. Dihydroethidium (DHE) was used to demonstrate in situ levels of superoxide production. JC-1 dye was used to measure changes in mitochondrial membrane potential. Activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) was determined by Bio-Plex immunoassay. TNF-alpha treatment significantly increased the mRNA and protein levels of VCAM-1 in HUVECs in a dose dependent manner. Rb1 pre-treatment effectively blocked the TNF-alpha-induced expression of VCAM-1 mRNA or protein by 80% and 43%, respectively (p<0.01). THP-1 adhesion was also blocked. Furthermore, Rb1 reduced the TNF-alpha-induced increase of superoxide anion production by 41% and inhibited the TNF-alpha-induced decrease of mitochondrial membrane potential by 44% in HUVECs. Rb1 also effectively blocked TNF-alpha-induced activation of p38, c-Jun N-terminal protein kinase, extracellular signal-regulated kinase 1/2 and IkappaBalpha. In conclusion, Rb1 effectively blocked the TNF-alpha-induced over-expression of VCAM-1, increased THP-1 adhesion and over-production of superoxide anion. Furthermore, Rb1 inhibited TNF-alpha-induced MAPKs and NF-kappaB activation. These data suggested that Rb1 might have potential therapeutic effects in controlling inflammation in vascular diseases.     

Paeonol suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells by blocking p38, ERK and nuclear factor-kappaB signaling pathways

Paeonol (2'-hydroxy-4'-methoxyacetophenone), the main active compound of the traditionally used Chinese herb Paeonia lactiflora Pallas, has anti-inflammatory, antioxidant and cardiovascular protective activities. We studied how the levels of intercellular adhesion molecule-1 (ICAM-1), one of the key molecules in the development of atherosclerosis, might be affected by paeonol in tumor necrosis factor-alpha (TNF-alpha)-activated human umbilical vein endothelial cells (HUVECs). Paeonol concentration-dependently inhibited the production of ICAM-1; it inhibited nuclear factor-kappaB (NF-kappaB) p65 translocation into the nucleus and the phosphorylation of inhibitory factor kappaBalpha (IkappaBalpha). It also blocked the TNF-alpha-induced phosphorylation of p38 and extracellular signal-regulated kinase (ERK), which are involved in regulating ICAM-1 production by TNF-alpha. Paeonol inhibited U937 monocyte adhesion to HUVECs stimulated by TNF-alpha, suggesting that it may inhibit the binding of monocytes to endothelium by regulating the production of critical adhesion molecules by TNF-alpha. The inhibitory effect of paeonol on ICAM-1 production might be mediated by inhibiting p38, ERK and NF-kappaB signaling pathways, which are involved in TNF-alpha-induced ICAM-1 production. Thus, paeonol may be beneficial in the treatment of cardiovascular disorders such as atherosclerosis.     

Possible mechanism of the anti-inflammatory activity of ruscogenin: role of intercellular adhesion molecule-1 and nuclear factor-kappaB

Ruscogenin (RUS), first isolated from Ruscus aculeatus, also a major steroidal sapogenin of traditional Chinese herb Radix Ophiopogon japonicus, has been found to exert significant anti-inflammatory and anti-thrombotic activities. Our previous studies suggested that ruscogenin remarkably inhibited adhesion of leukocytes to a human umbilical vein endothelial cell line (ECV304) injured by tumor necrosis factor-alpha (TNF-alpha) in a concentration-dependent manner. Yet the underlying mechanisms remain unclear. In this study, the in vivo effects of ruscogenin on leukocyte migration and celiac prostaglandin E(2) (PGE(2)) level induced by zymosan A were studied in mice. Furthermore, the effects of ruscogenin on TNF-alpha-induced intercellular adhesion molecule-1 (ICAM-1) expression and nuclear factor-kappaB (NF-kappaB) activation were also investigated under consideration of their key roles in leukocyte recruitment. The results showed that ruscogenin significantly suppressed zymosan A-evoked peritoneal total leukocyte migration in mice in a dose-dependent manner, while it had no obvious effect on PGE(2) content in peritoneal exudant. Ruscogenin also inhibited TNF-alpha-induced over expression of ICAM-1 both at the mRNA and protein levels and suppressed NF-kappaB activation considerably by decreasing NF-kappaB p65 translocation and DNA binding activity. These findings provide some new insights that may explain the possible molecular mechanism of ruscogenin and Radix Ophiopogon japonicus for the inhibition of endothelial responses to cytokines during inflammatory and vascular disorders.     

Inhibitors of 5-lipoxygenase inhibit expression of intercellular adhesion molecule-1 in human melanoma cells

INTRODUCTIONAlthough malignant melanoma accounts for lessthan 5 % of all cancers, it is among the most lethalbecause of its extremely high metastatic propensity[1-3].Metastasis develops after melanoma cancer cells com-plete a complex sequence of events which include dis-sociation from the primary cancer, invasion and sur-vival in the circulation and extravasation and prolifera-tion at a second site[4]. At each step during the cascade,melanoma cancer cells interact with various host cells.…     

Gamma-irradiation-induced intercellular adhesion molecule-1 (ICAM-1) expression is associated with catalase: activation of Ap-1 and JNK

The ionizing radiation used in cancer therapy frequently produces damage to normal tissues and induces complex responses, including inflammation. The upregulation of the intercellular adhesion molecule-1 (ICAM-1) in response to numerous inducing factors is associated with inflammation. Therefore, this study examined the molecular mechanisms responsible for ICAM-1 expression induced by gamma-irradiation (gammaIR). ICAM-1 mRNA and cell surface expression were induced in A549 human lung epithelial cells after exposing them to gammaIR. Catalase expression and activity were also increased in gammaIR-treated cells. Treatment of the gammaIR-treated cells with catalase resulted in a significant increase in the ICAM-1 cell surface expression level. The catalase inhibitor 3-amino-1,2,4-triazole (AT) reduced the level of ICAM-1. Electrophoretic mobility shift assay (EMSA) analysis showed that activating protein 1 (AP-1) was activated by gammaIR, whereas NF-kappaB was not. Specific Jun N-terminal kinase (JNK) inhibition attenuated the upregulation of gammaIR stimulated ICAM-1. Western blot analysis revealed a marked elevation in activation of JNK. In addition, pretreatment with AT resulted in a decrease in the level of JNK phosphorylation and AP-1 activation. Overall, data suggest that induction of ICAM-1 expression by gammaIR is associated with catalase. Furthermore, catalase, JNKs, and AP-1 activation induce ICAM-1 upregulation through a sequential process.     

细胞间粘附因子-1在非小细胞肺癌表达的临床意义

目的探讨细胞间粘附因子-1(Intercellular adhesion m olecule-1,ICAM-1)在肺癌组织中的表达及其与肺癌侵袭转移和预后的关系。方法回顾性分析86例非小细胞肺癌患者的手术切除标本,采用免疫组化SP法检测肺癌组织中的ICAM-1的表达,用χ2检验分析其表达与肺癌生物学行为的关系;生存分析用Kaplan-M eier生存曲线和Log-Rank检验。结果肺癌组织ICAM-1表达率为37.21%,鳞癌表达略高于腺癌;淋巴转移的肺癌组织ICAM-1表达率高于无淋巴结转移者;Ⅰ期肺癌中ICAM-1阳性率高于Ⅱ期,Ⅱ期高于Ⅲ期;术后转移组ICAM-1的阳性表达率低于无转移组;ICAM-1阳性表达患者术后转移率低于阴性患者;ICAM-1阳性表达的患者5年生存率高于ICAM-1阴性表达患者。结论非小细胞肺癌组织中ICAM-1的表达与病理类型无关;与病理分期、淋巴转移呈负相关;与术后患者血行转移和生存时间呈负相关。ICAM-1是判断非小细胞肺癌患者转移和预后的重要因素。     

Glabridin suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells by blocking sphingosine kinase pathway: implications of Akt, extracellular signal-regulated kinase, and nuclear factor-kappaB/Rel signaling pathways

(R)-4-(3,4-Dihydro-8,8-dimethyl)-2H,8H-benzo[1,2-b:3,4-b'] dipyran-3yl)-1,3-benzenediol (glabridin) is known to have anti-inflammatory, antimicrobial, and cardiovascular protective activities. In the present study, we report the inhibitory effect of glabridin on intercellular adhesion molecule-1 (ICAM-1) expression in tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs). Glabridin inhibited THP-1 cell adhesion to HUVECs stimulated by TNF-alpha and cell surface expression of ICAM-1 in TNF-alpha-stimulated HUVECs. The mRNA expression of adhesion molecules, including ICAM-1, vascular cell adhesion molecule-1, and E-selectin, was also suppressed by glabridin. Further study demonstrated the inhibitory effect of glabridin on nuclear factor (NF)-kappaB/Rel DNA binding, inhibitory factor-kappaB alpha (IkappaB alpha), and IkappaB beta degradation, IkappaB kinase activation, and p65 nuclear translocation in TNF-alpha-stimulated HUVECs. Treatment of a variety of cell lines with glabridin revealed that inhibitory effect of glabridin on NF-kappaB/Rel activation is not cell type-specific, and both inducible and constitutive NF-kappaB/Rel activation was suppressed by glabridin treatment. Moreover, TNF-alpha-induced phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was blocked by glabridin treatment in HUVECs. Glabridin also suppressed sphingosine-1-phosphate (S1P)-induced cell surface expression and mRNA expression of ICAM-1. Further study demonstrated that TNF-alpha-induced sphingosine kinase activity was inhibited by glabridin, and the inhibitory effect of glabridin on TNF-alpha-induced ICAM-1 expression was reversed by addition of exogenous S1P. Together, our results indicate that the inhibitory effect of glabridin on ICAM-1 expression might be mediated, at least in part, by inhibiting sphingosine kinase pathway and subsequent inhibition of signaling pathways, including Akt, ERK, and NF-kappaB/Rel signaling pathway.     

细胞间粘附分子-1与亚临床绒毛膜羊膜炎的关系探讨

目的研究细胞间粘附分子-1（ICAM-1）与亚临床绒毛膜羊膜炎的关系。方法采用免疫组织化学方法检测ICAM-1在胎膜早破组及相对应孕周末破膜妊娠组（对照组）胎膜中的表达,同时将所有病例的胎膜进行病理组织学检查。结果 ICAM-1在胎膜早破组中的表达明显高于对照组,两者差异有显著意义（P〈0.05）,而且在发生绒毛膜羊膜炎的研究组中表达更高,两者差异有极显著意义（P〈0.01）,胎膜早破组中绒毛膜羊膜炎的发生率（64.15%）明显高于对照组（20.00%）。结论细胞间粘附分子-1在胎膜早破组中的表达明显增高,其表达程度与感染程度相关。     

Tumour necrosis factor-alpha-induced ICAM-1 expression in human vascular endothelial and lung epithelial cells: modulation by tyrosine kinase inhibitors.

1. Tumour necrosis factor-alpha (TNF alpha) increases the expression of the adhesion molecule intercellular adhesion molecule-1 (ICAM-1) on cultured endothelial and epithelial cells and modulation of this may be important in controlling inflammation. Activation of tyrosine kinase(s) is known to be involved in the signal transduction pathways of many cytokines. In this study we have investigated the effects of the tyrosine kinase inhibitors, ST638, tyrphostin AG 1288 and genistein, on TNF alpha-induced ICAM-1 expression in human alveolar epithelial (A549) and vascular endothelial (EAhy926) cell lines and also normal human lung microvascular endothelial cells (HLMVEC). 2. ICAM-1 expression on cultured cells was determined by a sensitive enzyme-linked immunosorbant assay (ELISA). Endothelial or epithelial monolayers were exposed to increasing doses of TNF-alpha (0.01-10 ng ml-1), in the presence or absence of either ST638 (3-100 microM), AG 1288 (3-100 microM) or genistein (100 microM) and ICAM-1 expression was measured at 4 and 24 h. Control experiments examined the effect of ST638 on phorbol 12-myristate 13-acetate (PMA, 20 ng ml-1, 4 h)-stimulated ICAM-1 and compared it to that of a specific protein kinase C inhibitor, R031-8220 (10 microM). Also, functional consequences of changes in ICAM-1 expression were assessed by measuring adhesion of 111 In-labelled human neutrophils to EAhy926 endothelial and A549 epithelial monolayers treated with TNF alpha, in the presence or absence of ST638. 3. ST638 caused a concentration-dependent reduction in TNF alpha- (0.1-10 ng ml-1)-induced ICAM-1 on EAhy926 endothelial (at 4 h) and A549 epithelial monolayers (at 4 and 24 h). In contrast, ST638 caused a concentration-dependent increase in TNF alpha- (0.1-10 ng ml-1)-induced ICAM-1 on EAhy926 endothelial cells at 24 h. Similar effects were seen with AG 1288 or genistein. ST638 (100 microM) significantly (P < 0.01) inhibited ICAM-1 expression on HLMVEC endothelial cells induced by 0.01 ng ml-1 TNF alpha at 4 or 24 h or 0.1 ng ml-1 at 4 h, but increased ICAM-1 expression induced by 0.1 ng ml-1 TNF alpha at 24 h. ST638 did not significantly change the expression of PMA-stimulated ICAM-1 on either A549 epithelial, EAhy926 or HLMVEC endothelial cells. However, PMA-induced ICAM-1 expression was inhibited by Ro31-8220. Also, treatment of epithelial or endothelial monolayers with TNF alpha and ST638 altered adhesion of human neutrophils to A549 epithelial or EAhy926 endothelial cells in a manner that corresponded to the alteration in ICAM-1 expression. 4. These results show that tyrosine kinase inhibitors alter TNF alpha-induced ICAM-1 expression, but that the cell type, concentration of TNF alpha and time of exposure to this cytokine determine whether expression is decreased or increased by the inhibitor. An increased understanding of the signal transduction pathway(s) involved in TNF alpha-induced ICAM-1 expression on lung epithelial and vascular endothelial cells may be of potential therapeutic value in the treatment of inflammatory disease.     

褪黑素对梗阻性黄疸肠组织ICM-1表达的影响

目的探讨褪黑素对大鼠梗阻性黄疸后肠组织细胞间粘附分子-1(ICAM-1)表达的影响。方法将36只大鼠随机分为3组(每组12只):假手术对照组(SO)、梗阻性黄疸组(OJ)、褪黑素治疗组(MT)。观察各组小肠组织中ICAM-1的表达及小肠组织形态学改变,并测量肠绒毛高度和黏膜厚度。结果梗阻性黄疸组小肠组织ICAM-1的表达明显增强,肠绒毛高度、黏膜厚度明显降低,与假手术对照组有显著性差异(P<0.01,P<0.01);褪黑素治疗组与梗阻性黄疸组比较小肠组织ICAM-1的表达明显减弱(P<0.01),肠绒毛高度、黏膜厚度增高,肠组织结构损害减轻(P<0.01)。结论褪黑素通过抑制梗阻性黄疸后肠组织ICAM-1的表达,减轻小肠黏膜的损伤。     

Endothelin-1 enhances vascular cell adhesion molecule-1 expression in tumor necrosis factor alpha-stimulated vascular endothelial cells

Vascular cell adhesion molecule-1 (VCAM-1) is a mononuclear leukocyte-selective adhesion molecule that is expressed in human vascular endothelial cells at sites of local inflammation. It participates in local endothelial-monocyte interactions during the initiation of atherosclerosis. In the present study, endothelin alone did not induce the surface expression and mRNA accumulation of VCAM-1 in human vascular endothelial cells, but inhibition of endogenous nitric oxide (NO) by N(G)-monomethyl-L-arginine enhanced the surface expression and mRNA accumulation of VCAM-1 stimulated by endothelin-1. It is conceivable that in human vascular endothelial cells, stimulation of an endothelin receptor results in the production of nitric oxide (NO), suppressing the expression of VCAM-1. Endothelin-1 enhanced the surface expression and mRNA accumulation of VCAM-1 in cells treated with tumor necrosis factor alpha (TNF-alpha). The enhancement by endothelin-1 may be explained by the inhibitory effect of TNF-alpha on endothelin-induced NO production. Pretreatment with BQ788 (an endothelin ET(B) receptor antagonist) or inhibitors of nuclear factor kappa B (NF-kappaB) activation completely diminished the synergistic enhancement of VCAM-1 expression by endothelin-1 in TNF-alpha-stimulated vascular endothelial cells, both at the protein and mRNA levels. These findings suggest that the synergistic enhancement of VCAM-1 expression by TNF-alpha and endothelin ET(B) receptor stimulation may be augmented by the induction of NF-kappaB binding activity in human vascular endothelial cells.     

贝纳普利对糖尿病大鼠肾脏中ICAM-1 mRNA和尿微量白蛋白的影响

目的探讨血管紧张素转换酶抑制剂贝纳普利对糖尿病肾脏病变的保护作用和对细胞间粘附分子(ICAM-1)mRNA及蛋白表达的影响.方法STZ诱发大鼠糖尿病,实验设正常组,糖尿病对照组,贝纳普利组和胰岛素治疗组,贝纳普利1.1mg·kg-1·d-1治疗2月,观察肾脏肥大、尿蛋白变化以及用免疫组化和RT-PCR方法检测ICAM-1在肾组织的定位、半定量表达.结果与糖尿病组相比,贝纳普利能显著降低肾重/体重,24h尿微量白蛋白(P<0.01).免疫组化和RT-PCR半定量结果显示贝纳普利能显著降低ICAM-1表达(P<0.01).结论贝纳普利能够降低STZ诱发糖尿病大鼠肾脏组织ICAM-1 mRNA和蛋白表达,对糖尿病肾脏病变有保护作用.