共查询到20条相似文献,搜索用时 31 毫秒
1.
Signal pathways underlying homocysteine-induced production of MCP-1 and IL-8 in cultured human whole blood 总被引:4,自引:0,他引:4
Aim: To elucidate the mechanisms underlying homocysteine (Hcy)-induced chemokine production. Methods: Human whole blood was pretreated with inhibitors of calmodulin (CAM), protein kinase C (PKC), protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and NF-kB and activators of PPARγ for 60 min followed by incubation with Hcy 100 μmol/L for 32 h. Thelevels of mitogen chemokine protein (MCP)-I and interleukin-8 (IL-8) were determined by enzyme-linked immunosorbant assay (ELISA). Results: Inhibitors of PKC (calphostin C, 50-500 nmol/L and RO-31-8220, 10-100 nmol/L), CaM (W7, 28-280 μmol/L), ERK1/2 MAPK (PD 98059, 2-20 μmol/L), p38 MAPK (SB 203580, 0.6-6μmol/L), JNK MAPK (curcumin, 2-10μmol/L), and NF-kB(PDTC, 10-100 nmol/L) markedly reduced Hcy 100 μmol/L-induced production of MCP-1 and IL-8 in human cultured whole blood, but the inhibitors of PTK(genistein, 2.6-26 μmol/L and tyrphostin, 0.5-5 μmol/L) had no obvious effect on MCP-1 and IL-8 production. PPARγ activators (ciglitazone 30 μmol/L andtroglitazone 10 μmol/L) depressed the Hcy-induced MCP-1 production but not IL-8 production in the cultured whole blood. Conclusion: Hcy-induced MCP-1 and IL-8 production is mediated by activated signaling pathways such as PKC, CaM, MAPK, and NF-kB. Our results not only provide clues for the signal transduction pathways mediating Hcy-induced chemokine production, but also offer a plausible explanation for a pathogenic role of hyperhomocysteinemia in these diseases. 相似文献
2.
Homocysteine induces production of monocyte chemoattractant protein-1 and interleukin-8 in cultured human whole blood 总被引:13,自引:1,他引:12
AIM: To investigate whether increased plasma L-homocysteine (Hcy) level could promote monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in cultured whole blood. METHODS: Human whole blood or different type of peripheral blood cells from health volunteers were incubated with Hcy and/or the inhibitors. MCP-1 and IL-8 level were measured by ELISA assay. RESULTS: Hcy 10-1000μmol/L induced production of MCP-1 and IL-8 in cultured human whole blood (P<0.05). The major cellular source of these chemokines corned from monocytes. Meanwhile,Hcy also promoted the upregulation of MPO level even at the 10 μmol/L in the cultured whole blood. The intracellular ROS, particular the OH' radicals, play extremely important role in the Hcy-induced MCP-1 and IL-8 production. CONCLUSION: Increased Hcy level in plasma (hyperhomocysteinemia) induced MCP-1 and IL-8 secretion in cultured human whole blood, especially in monocytes via oxidative stress mechanism. 相似文献
3.
目的 观察离体急性冠状动脉综合征 (ACS)病人外周血单个核细胞对C 反应蛋白 (CRP)直接刺激的反应性及亲水性他汀 (普伐他汀 )与亲脂性他汀 (氟伐他汀 ,辛伐他汀 )药物干预后的效果。方法 离体培养ACS(n =15 )病人、稳定型心绞痛 (SAP)病人 (n =13)与健康人 (n =15 )外周血单个核细胞 ,CRP(2 0mg·L-1)刺激细胞 2 4h后检测细胞培养液上清中IL 6的表达 (ELISA)。普伐他汀、氟伐他汀、辛伐他汀分别按照不同浓度 (1× 10 -6,2 5× 10 -6,5× 10 -6,7 5× 10 -6,1× 10 -5mol·L-1)预先孵育细胞 2h后继以CRP刺激 2 4h ,ELISA分析培养液上清中的IL 6水平。结果 CRP(2 0mg·L-1)明显激活ACS病人外周血单个核细胞IL 6的表达。健康组、SAP组和与ACS组IL 6表达分别为(987± 10 2 )ng·L-1,(991± 134)ng·L-1,(312 9± 333)ng·L-1,均较其基础状态 (未受CRP刺激 )明显增高 (P <0 0 5 ) ;受CRP刺激状态下 ,ACS组IL 6表达是健康组的数倍(P <0 0 5 )。ACS病人外周血单个核细胞在不同剂量普伐他汀、氟伐他汀、辛伐他汀药物干预下 ,IL 6表达下降水平有所不同。结论 一定浓度的CRP能直接诱导人外周血单个核细胞IL 6表达增加 ,提示CRP能直接激活炎症反应 ,在ACS及其并发症的病理机制中可能发挥重要作用。他汀类药? 相似文献
4.
JEAN LOUIS MEGNIEN ALAIN SIMON ANTONIA ANDRIANI PATRICK SEGOND SOPHIE JEANNIN & JAIME LEVENSON 《British journal of clinical pharmacology》1996,42(2):187-193
1 We tested whether lipid lowering treatment with HMG CoA reductase inhibitor modified the flow mediated large artery reactivity in primary pure hypercholesterolaemia.
2 Abnormalities in arterial reactivity have been described in the presence of high blood cholesterol, in particular an enhanced constriction of the brachial artery in response to acute induction of a low flow state.
3 Using pulsed-Doppler, we measured brachial artery diameter and flow velocity at rest and their changes induced by wrist occlusion before and after 3 months of double-blind treatment by pravastatin (40 mg orally) in 13 subjects and placebo in 15 others.
4 The significant decrease ( P <0.01) in diameter induced by wrist occlusion before (0.34±0.08 mm) placebo and pravastatin (0.39±0.10 mm) persisted after placebo (0.26±0.07 mm) but was abolished after pravastatin (0.07±0.05 mm). The absolute change in diameter induced by wrist occlusion was lower after than before pravastatin ( P <0.01) and lower after pravastin than after placebo ( P <0.05). Diameter during wrist occlusion was higher after pravastatin than after placebo (4.35±0.16 vs 3.89±0.09 mm); P <0.01).
5 These findings indicate that the lipid changes induced by pravastatin and/or some unknown but direct mechanism of the drug itself inhibit low-flow-mediated vasoconstriction associated with hypercholesterolaemia. Such effects may have important implications for the treatment of vasospasm often seen in the presence of high blood cholesterol. 相似文献
2 Abnormalities in arterial reactivity have been described in the presence of high blood cholesterol, in particular an enhanced constriction of the brachial artery in response to acute induction of a low flow state.
3 Using pulsed-Doppler, we measured brachial artery diameter and flow velocity at rest and their changes induced by wrist occlusion before and after 3 months of double-blind treatment by pravastatin (40 mg orally) in 13 subjects and placebo in 15 others.
4 The significant decrease ( P <0.01) in diameter induced by wrist occlusion before (0.34±0.08 mm) placebo and pravastatin (0.39±0.10 mm) persisted after placebo (0.26±0.07 mm) but was abolished after pravastatin (0.07±0.05 mm). The absolute change in diameter induced by wrist occlusion was lower after than before pravastatin ( P <0.01) and lower after pravastin than after placebo ( P <0.05). Diameter during wrist occlusion was higher after pravastatin than after placebo (4.35±0.16 vs 3.89±0.09 mm); P <0.01).
5 These findings indicate that the lipid changes induced by pravastatin and/or some unknown but direct mechanism of the drug itself inhibit low-flow-mediated vasoconstriction associated with hypercholesterolaemia. Such effects may have important implications for the treatment of vasospasm often seen in the presence of high blood cholesterol. 相似文献
5.
目的:研究吗啡对人外周血中肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)含量的影响,探讨其对免疫炎症反应的可能机制。方法:全血收集在试管内,分装在EP管中,每管取100μl全血。实验分为吗啡200mg.L^-1组(A1组)、吗啡2mg.L^-1组(A2组)、吗啡200mg.L^-1+脂多糖(LPS)(B1组)、吗啡2mg.L^-1组+LPS(B2组)、对照组(C1组)和LPS组(C2组)共6组(n=7)。各组加入上述试剂,用PBS补齐体积后,在37℃下孵育6h。用ELISA检测血清中TNF-α和IL-6含量。结果:单独药物组(A1和A2组)TNF-α的浓度分别为240和251ng.L^-1与空白对照组(C1组,TNF-α的浓度为279ng.L^-1)比较,无显的统计学意义(P>0.05);IL-6的浓度分别为444、490和561ng.L^-1,亦无统计学意义(P>0.05),激活组(B1和B2组)和LPS组(C2组)分别为490、534和1226ng.L^-1(TNF-α);1177、1310和1563ng.L^-1(IL-6)。且B1组低于B2组。结论:吗啡对静息状态下TNF-α的表达无影响,但可抑制LPS诱导的TNF-α表达,且高剂量的吗啡对LPS诱导的TNF-α的抑制作用大于低剂量吗啡的作用。 相似文献
6.
Chang LT Sun CK Chiang CH Wu CJ Chua S Yip HK 《Journal of cardiovascular pharmacology》2007,49(1):20-26
Antiinflammatory properties of losartan are currently unclear. This study tested the hypothesis that losartan itself has an antiinflammatory effect comparable to that of simvastatin. Human umbilical vein endothelial cells (HUVECs) were (1) incubated with culture medium alone, (2) incubated with added C-reactive protein (CRP) (25, 50, 75, and 100 microg/mL) for stimulation, and (3) pretreated with losartan (stepwise increased dose: 100, 300, 500, and 750 micromol/L) and simvastatin (stepwise increased dose: 25, 50, 75, and 100 micromol/L) for 4 hours before adding CRP for stimulation. Surface expression of vascular cell adhesion molecule-1 (VCAM-1) was determined by flow cytometry. Supernatant levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) were measured by ELISA. Experimental results showed that the effect of CRP on VCAM-1 expression and supernatant levels of MCP-1 and IL-6 increases stepwise as CRP concentrations increase from 25 to 50 to 75 to 100 microg/mL (all P < 0.001). The effect of CRP on VCAM-1 expression in HUVECs and supernatant levels of MCP-1 and IL-6 were significantly suppressed by 25 micromol/L simvastatin with stepwise increased suppression as simvastatin dose increased to 50, 75, and 100 micromol/L (all P < 0.0001). However, losartan did not significantly suppress CRP's effect on VCAM-1 expression in HUVECs (P > 0.5). Moreover, losartan did not suppress CRP's effect on MCP-1 and IL-6 secretion unless a high dose (> or =500 micromol/L) of losartan was used. Compared with simvastatin, losartan had less effect on suppression of CRP-mediated inflammation. 相似文献
7.
Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) have been reported to contribute to the pathogenesis of many inflammatory diseases, e.g., rheumatoid arthritis. As monocytes are believed to be the primary source of these cytokines in peripheral blood, the present study was conducted to establish ranges and patterns of IL-1 beta and TNF-alpha secretion. Using heparinized unseparated whole blood obtained from normal human volunteers, peripheral blood monocytes were stimulated with Sal. minnesota LPS or BSA/anti-BSA immune complex-coated beads (BSA-beads). ELISAs for IL-1 beta and TNF-alpha were employed to quantitate cytokine levels in blood plasma without performing arduous and time-consuming extraction procedures. Over the course of a 6 hr incubation, LPS elicited a dose-dependent increase in TNF-alpha and IL-1 beta production. Preincubation of whole blood with interferon-gamma prior to the addition of a suboptimal dose of LPS or BSA-beads resulted in a synergistic potentiation of IL-1 beta/TNF-alpha production. Dexamethasone, utilized in the treatment of rheumatoid arthritis, proved to be a potent inhibitor of cytokine biosynthesis in whole blood ex vivo. The measurement of cytokine biosynthesis in a relevant physiologic environment not only avoids non-specific monocyte activation, but also may increase our ability to predict clinical outcomes in rheumatoid arthritis and/or other inflammatory diseases. 相似文献
8.
Francis F. Tukov Jane F. Maddox David E. Amacher Walter F. Bobrowski Robert A. Roth Patricia E. Ganey 《Toxicology in vitro》2006,20(8):1488-1499
Xenobiotic–inflammation interactions lead to hepatotoxicity in vivo. Selected xenobiotic agents (acetaminophen, APAP; chlorpromazine, CPZ; allyl alcohol, AlOH; monocrotaline, MCT) for which this occurs were evaluated for ability to elicit the release of Kupffer cell (KC)-derived inflammatory mediators and to modulate lipopolysaccharide (LPS)-stimulated release of these mediators. Using KCs and hepatocytes (HPCs) isolated from rat, KC/HPC cocultures were treated with either LPS, xenobiotic, vehicle or a combination. Six hours later, the release of inflammatory mediators was assessed. LPS alone caused a concentration-dependent increase in TNF- release but had no significant effect on the release of PGE2. APAP by itself did not alter release of TNF-, PGE2, IL-10, Gro/KC or IFN-γ; however, in the presence of LPS, APAP enhanced LPS-induced TNF- and Gro/KC release. APAP also attenuated LPS-induced increases in IL-10 and MCP-1. CPZ alone caused a concentration-dependent increase in TNF- release, which was approximately additive in the presence of LPS. AlOH alone did not affect TNF- release, but decreased TNF- production in the presence of LPS. AlOH increased PGE2 production, and this effect was potentiated in the presence of LPS. MCT by itself did not affect release of TNF- but increased the response to LPS. Neither MCT, LPS, nor the combination affected production of PGE2. These results demonstrate that KC/HPC cocultures can be used to evaluate interactions of xenobiotics with LPS. Furthermore, data from these studies qualitatively mirror reported data from whole animal studies, suggesting that this model could be useful for predicting aspects of xenobiotic–inflammation interactions in vivo. 相似文献
9.
C-reactive protein augments interleukin-8 secretion in human peripheral blood monocytes 总被引:1,自引:0,他引:1
C-reactive protein (CRP) is a powerful predictor and risk factor for cardiovascular diseases. The CXC- and CC-type chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) are important chemokines for leukocyte trafficking identified in atheromatous plaque expressed mainly by macrophages in humans. We assessed whether C-reactive protein could induce MCP-1 and IL-8 secretion. In human peripheral blood monocytes, C-reactive protein (12.5-50 microg/mL) increased IL-8, but not MCP-1 secretion in a time- (6-24 hours) and dose-dependent manner as detected by ELISA. C-reactive protein could augment the production of reactive oxygen species (ROS) as measured by chemiluminescence and inhibitors of NAD(P)H oxidase (DPI and PAO) and ROS scavengers (superoxide dismutase, catalase, and 1% dimethyl sulphoxide) abolished C-reactive protein-induced IL-8 secretion. Furthermore, relative quantity of IL-8 mRNA was significantly increased by C-reactive protein 50 microg/mLfor 12 hours, which could be inhibited by DPI 1 microM or superoxide dismutase (SOD) 250 U/mL. The inhibitors of ERK 1/2 (PD98059), p38 (SB203580) MAPK, and NF-kappaB (PDTC and MG132) significantly decreased C-reactive protein-induced IL-8 secretion in human monocytes. Also, agonists of peroxisome proliferator-activated receptor (PPAR) alpha (WY14643) and PPARgamma (troglitazone) could largely inhibit C-reactive protein responses. Thus, our data indicate that C-reactive protein at pathologic levels increases IL-8 secretion and mRNA via enhancing ROS derived mainly from NAD(P)H oxidase and the subsequent activation of ERK1/2, p38 MAPK, and NF-kappaB. The activation of PPARalpha/gamma can negatively regulate C-reactive protein-induced IL-8 production in human monocytes. 相似文献
10.
Transfer of methylamphetamine and amphetamine into breast milk following recreational use of methylamphetamine 总被引:2,自引:1,他引:1
Anne Bartu Leon J. Dusci & Kenneth F. Ilett 《British journal of clinical pharmacology》2009,67(4):455-459
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The extent of drug transfer into milk during recreational intravenous use of methylamphetamine has not previously been studied.
WHAT THIS STUDY ADDS
• We have shown that methylamphetamine transfers into breast milk.
• The amount a breastfed infant would receive varied over 2.5-fold range.
• A 48-h withholding period for breastfeeding is recommended following recreational use.
AIMS To investigate the transfer of amphetamines into breast milk following their recreational use and estimate drug exposure for the breastfed infant.
METHODS Two breastfeeding mothers who were occasional recreational users of intravenous amphetamines were studied. A urine sample was collected 4 h after dose, and milk samples were collected over 24 h. Drug in urine was qualitatively identified by gas chromatography-mass spectrometry and quantification in milk was by high-performance liquid chromatography. Absolute infant dose via milk was estimated.
RESULTS The urines contained predominantly methylamphetamine together with smaller amounts of amphetamine. In the 24 h after dose, average concentrations in milk were 111 µg l−1 and 281 µg l−1 for methylamphetamine and 4 µg l−1 and 15 µg l−1 for amphetamine in cases 1 and 2, respectively. Absolute infant doses for methylamphetamine plus amphetamine (as methylamphetamine equivalents) were 17.5 µg kg−1 day−1 and 44.7 µg kg−1 day−1 , respectively, for cases 1 and 2.
CONCLUSION These limited data suggest that breastfeeding should be withheld for 48 h after recreational amphetamine use. 相似文献
• The extent of drug transfer into milk during recreational intravenous use of methylamphetamine has not previously been studied.
WHAT THIS STUDY ADDS
• We have shown that methylamphetamine transfers into breast milk.
• The amount a breastfed infant would receive varied over 2.5-fold range.
• A 48-h withholding period for breastfeeding is recommended following recreational use.
AIMS To investigate the transfer of amphetamines into breast milk following their recreational use and estimate drug exposure for the breastfed infant.
METHODS Two breastfeeding mothers who were occasional recreational users of intravenous amphetamines were studied. A urine sample was collected 4 h after dose, and milk samples were collected over 24 h. Drug in urine was qualitatively identified by gas chromatography-mass spectrometry and quantification in milk was by high-performance liquid chromatography. Absolute infant dose via milk was estimated.
RESULTS The urines contained predominantly methylamphetamine together with smaller amounts of amphetamine. In the 24 h after dose, average concentrations in milk were 111 µg l
CONCLUSION These limited data suggest that breastfeeding should be withheld for 48 h after recreational amphetamine use. 相似文献
11.
12.
The study was designed to examine whether the hydrophilic statin - pravastatin and the hydrophobic statin - simvastatin affect colon cancer cell-induced cytokine secretion by peripheral blood mononuclear cells (PBMC). Statins were added to human colon cancer cells (HT-29 and RKO), or to PBMC incubated separately or jointly. The secretion of the pro-inflammatory cytokines IL-1β and IFNγ and that of the anti-inflammatory cytokines IL-1ra and IL-10 induced by cancer cells was decreased by simvastatin but not by pravastatin, whereas that of IL-6 was not affected by both drugs. Conditioned media from colon cancer cells incubated with either simvastatin or pravastatin induced stimulation of cytokine production by PBMC similar to that caused by conditioned media derived from cancer cells incubated without the drugs, suggesting that simvastatin acts directly on the interaction between cancer and PBM cells. Simvastatin, but not pravastatin, caused inhibition of both cancer cell proliferation. The results imply that simvastatin may affect inflammation-induced colon cancer proliferation via alteration of the equilibrium between pro- and anti-inflammatory cytokines. 相似文献
13.
Soluble beta-1,3-glucan has been demonstrated to protect against infection and shock in rats and mice, and clinical studies suggest that administration of soluble glucans to trauma/surgical patients decreases septic complications and improves survival. However, little is known about the precise mechanisms by which glucans influence the state of activation of blood cells, which are responsible for the fulminant cytokine production and the activation of the coagulation system observed in serious gram-negative infection. We studied therefore the effect of an underivatized, soluble yeast beta-1,3-glucan and lipopolysaccharide (LPS), either alone or in combination, on tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-8 and IL-10 secretion and monocyte tissue factor (TF) expression in human whole blood. As expected, LPS induced the secretion of substantial amounts of all measured parameters, whereas only minor amounts of TNFalpha, IL-6, and IL-10 were induced by beta-glucan itself. However, beta-glucan itself induced the production of significant amounts of IL-8 and TF. Soluble beta-1,3-glucan had a strong synergistic effect on the LPS-induced secretion of IL-8, IL-10, and on monocyte TF activity, but not on TNFalpha and 1L-6 production. On the other hand, soluble beta-glucan strongly primed LPS stimulation of all parameters, including TNFalpha and IL-6. beta-Glucan also induced detectable neutrophil degranulation within 15 min, whereas a response to LPS was first detected after 90 min. In conclusion, soluble beta-1,3-glucan upregulated leukocyte activity, both on its own and in concert with LPS. 相似文献
14.
Licastro F Chiappelli M Porcellini E Trabucchi M Marocchi A Corsi MM 《International journal of immunopathology and pharmacology》2006,19(1):181-185
Downs syndrome (DS) is the most frequent human chromosomal abnormality and is associated with mental retardation. Some evidence indicates that certain inflammatory molecules may be increased in DS. Proinflammatory and vasoactive molecules in the blood of non demented subjects with DS were measured in the present investigation. Plasma levels of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1) and C reactive protein (CRP) were measured in child (2-14 years), adult (20-50 yrs) and elderly (> 60 yrs) DS subjects. Increased plasma levels of IL-6 and MCP-1 were present in DS. Plasma levels of VEGF were increased only in DS adults. Positive linear correlation between IL-6 and MCP-1 levels was present. However, no subclinical inflammation was apparent in DS, since neopterin and CRP levels were within the normal range. An altered regulation of these molecules might interfere with some processes involved in cognitive performances of DS subjects. 相似文献
15.
Ye Y Huang X Zhang Y Lai X Wu X Zeng X Tang X Zeng Y 《International immunopharmacology》2012,12(2):384-393
A rise in intracellular Ca2 + ([Ca2 +]i) is crucial for the activation of macrophages, however, the mechanisms and consequences of this [Ca2 +]i increase remain unclear. This study investigated the role of calcium in mouse peritoneal macrophages stimulated with LPS plus IFN-γ by using the store-operated Ca2 + channel (SOCC) blocker SK&;F 96365. Our results showed that SK&;F 96365 pretreatment significantly inhibited the elevation of [Ca2 +]i induced by ionomycin, thapsigargin, and LPS plus IFN-γ, respectively. Phagocytosis analyzing results showed that SK&;F 96365 efficiently diminished the uptake of nonopsonized 1 μM yellow-green beads or pHrodo?-labeled Escherichia coli bacteria both on the resting and LPS plus IFN-γ-stimulated macrophages. In addition, SK&;F 96365 significantly inhibited the LPS plus IFN-γ-induced brisk uptake of NO and ROS. The CBA analyzing results showed that SK&;F 96365 pretreatment efficiently inhibited the production of LPS plus IFN-γ-induced inflammatory cytokines of IL-6, MCP-1, TNF, INF-γ, and IL-10. However, SK&;F 96365 pretreatment did not inhibit but augment the production of LPS plus IFN-γ-induced IL-1β secretion. Furthermore, SK&;F 96365 pretreatment inhibited the LPS plus IFN-γ-induced translocation of NF-κB to the nucleus, and induced a decrease in mitochondrial membrane potential (ΔΨm) in LPS plus IFN-γ-activated macrophages. This study provides insight into the role of calcium in the activation of peritoneal macrophages induced by LPS plus IFN-γ, and blocking the calcium influx by SK&;F 96365 exhibited a domain inhibitory effect on the LPS plus IFN-γ-induced inflammatory response in macrophages. 相似文献
16.
Freyne EJ Lacrampe JF Deroose F Boeckx GM Willems M Embrechts W Coesemans E Willems JJ Fortin JM Ligney Y Dillen LL Cools WF Goossens J Corens D De Groot A Van Wauwe JP 《Journal of medicinal chemistry》2005,48(6):2167-2175
The influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma. We describe here the synthesis and pharmacological evaluation of a series of triazinylphenylalkylthiazolecarboxylic acid esters that were designed to act as lung-specific antedrugs and inhibitors of the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine. Closer examination of the hydroxypropyl ester, 15, indicated its high metabolic stability (t(1/2) > 240 min) in human lung S9 fraction but rapid conversion (t(1/2) = 15 min) into the pharmacologically inactive carboxylic acid by human liver preparations. In stimulated human whole blood cultures, 15 reduced not only the production of IL-5 (IC(50) = 78 nM) but also the biosynthesis of the monocyte chemotactic proteins MCP-1 (IC(50) = 220 nM), MCP-2 (IC(50) = 580 nM), and MCP-3 (IC(50) = 80 nM). In vivo, intratracheal administration of 15 (6 mg/animal) to allergic sheep, either before (-4 h) or after (+1.5 h) the pulmonary allergen challenge, completely abrogated the late-phase airway response and reduced the bronchial hyperreactivity to inhaled carbachol. 相似文献
17.
Uchiyama Y Yoshida H Koike N Hayakawa N Sugita A Nishimura T Mihara M 《International immunopharmacology》2008,8(11):1595-1601
We explored the mechanism for the increase of blood IL-6 level after anti-IL-6 receptor (IL-6R) antibody injection. First, we examined whether anti-IL-6R antibody stimulates IL-6 production. Single injection of tocilizumab (anti-IL-6R antibody) in monkeys with collagen-induced arthritis (CIA) caused a marked increase in blood IL-6 and IL-6R levels, but did not increase IL-6 mRNA and IL-6R mRNA expression in liver, spleen, lymph nodes, synovium or whole blood 1, 3 and 7 days later. This suggests that tocilizumab did not induce IL-6 and IL-6R production. Second, we investigated whether anti-IL-6R antibody releases IL-6 from IL-6 complexes in the blood. When plasma from CIA monkeys was incubated with tocilizumab, the IL-6 concentration was not affected. Finally, we studied whether anti-IL-6R antibody affects the clearance of IL-6 from the blood. When MR16-1 (anti-mouse IL-6R antibody) was injected into IL-6-deficient mice continuously infused with human IL-6, blood human IL-6 levels significantly increased. These results suggest that the elevation of blood IL-6 after the administration of anti-IL-6R antibody is the result of inhibition of the clearance of IL-6 due to IL-6R blockade, and that it is not the result of induction of IL-6 production or release of IL-6 from complexes. 相似文献
18.
This study investigated the effect of in vitro exposure to caffeine, and its major metabolite paraxanthine, at concentrations relevant to typical caffeine consumption in humans, on lipopolysaccharide (LPS)-stimulated cytokine production in human whole blood. In addition, a role for the cyclic AMP/protein kinase A (PKA) pathway in the immunomodulatory effect of caffeine was investigated. Diluted whole blood (taken following >/=15 h abstinence from caffeine-containing food and beverages) was preincubated with caffeine or paraxanthine (10-100 microM) and stimulated with LPS (1 proportional, variant g/ml) for 24 h. The proinflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-12, and the antiinflammatory cytokine IL-10 were measured in cell-free supernatants. Whilst caffeine and paraxanthine had little or no effect on IL-10, IL-1beta, or IL-12 production, TNF-alpha production was suppressed in all individuals studied. The effect was statistically significant at 100 microM and consistent across seven experiments performed. Although not statistically significant, a similar effect was observed with paraxanthine. Caffeine (100 microM) also increased intracellular cyclic AMP concentrations in LPS-stimulated monocytes isolated from whole blood. Moreover, the effect of caffeine on TNF-alpha production was abolished by pretreatment with the protein kinase A inhibitor Rp-8-Br-cAMPS (10(-4) and 10(-5)M). To conclude, this study demonstrates that concentrations of caffeine that are relevant to human consumption consistently suppress production of the proinflammatory cytokine TNF-alpha in human blood and that this effect is mediated by the cyclic AMP/protein kinase A pathway. 相似文献
19.
Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. 总被引:9,自引:0,他引:9
Curcumin, a dietary pigment responsible for the yellow colour of curry, has been used for the treatment of inflammatory diseases and exhibits a variety of pharmacological effects such as anti-inflammatory activity. The mechanism in anti-inflammatory activity of curcumin has been investigated; however, little is known about the effect of curcumin on cytokine production by human peripheral blood monocytes and alveolar macrophages. In the present study, we shed light on the effect of curcumin on inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. To this end, we determined the concentrations of interleukin-8 (IL-8), monocyte inflammatory protein-1 (MIP-1alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-1beta (IL-1beta), and tumour necrosis factor-alpha (TNF-alpha) in the culture supernatants from phorbor ester, 4beta phorbor 12beta-myristate-13alpha acetate (PMA)- or lipo-polysaccharide (LPS)-stimulated monocytes and alveolar macrophages in the presence or absence of curcumin. Curcumin inhibited the production of IL-8, MIP-1alpha, MCP-1, IL-1beta, and TNF-alpha by PMA- or LPS-stimulated monocytes and alveolar macrophages in a concentration- and a time-dependent manner. These results show that curcumin exhibits an inhibitory effect on the production of IL-8, MIP-1alpha, MCP-1, IL-1beta, and TNF-alpha by PMA- or LPS-stimulated monocytes and alveolar macrophages. 相似文献
20.
Xiao-Xu-Ming decoction extract alleviates LPS-induced neuroinflammation associated with down-regulating TLR4/MyD88 signaling pathway in vitro and in vivo
下载免费PDF全文
![点击此处可从《中国药学》网站下载免费的PDF全文](/ch/ext_images/free.gif)
In the present study, we aimed to investigate the effects of Xiao-Xu-Ming decoction extract (XXM) on lipopolysaccaride (LPS)-induced neuroinflammation invitro and invivo. Invitro, the microglia BV2 cells were treated with 200 ng/mL LPS for 24 h to induce inflammatory responses. Invivo, mice were treated with 5 mg/kg LPS to induce inflammatory responses. The NO level was determined by Griess Reagents. The levels of IL-1β, IL-6, TNF-α and MCP-1 were determined by ELISA. The expressions of Iba-1, TLR4 and MyD88 at the protein levels were determined by Western blotting analysis. The mRNA levels of TLR4 and MyD88 were determined by real-time PCR. Invitro, XXMsignificantly reduced the levels of various pro-inflammatory factors, including NO, IL-1β, IL-6 and TNF-α, induced by LPS in the supernatant of BV2 cells and suppressedexpressions of inflammatory proteins TLR4 and MyD88 induced by LPS in BV2 cells. Invivo, XXM significantly inhibited microglia activation, attenuated LPS-induced inflammatory factors and chemokine production, such as IL-1β, IL-6, TNF-α and MCP-1, andinhibited the expressions of inflammatory proteins including TLR4 and MyD88, in the cortex of LPS-induced mice. Our findings suggested that XXM could attenuate LPS-induced neuroinflammation via down-regulating TLR4/MyD88 signaling pathway. 相似文献