Interleukin-1β-induced, nitric oxide-dependent and -independent inhibition of vascular smooth muscle contraction

Stimulation of vascular smooth muscle by bacterial lipopolysaccharide has been shown to produce interleukin-1β and to induce vasodilation in septic shock. To understand the mechanisms of interleukin-1β-induced relaxation, we examined the effects of interleukin-1β on contractility and cyclic GMP contents of vascular smooth muscle. After treatment of the rat aorta with interleukin-1β (20 ng/ml) for 6 h, the cyclic GMP content increased and the contraction induced by phenylephrine (1 μM) was partially inhibited. An inhibitor of nitric oxide (NO) synthase, N^G-monomethyl-

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-arginine (

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-NMMA, 100 μM), prevented the inhibitory effect of interleukin-1β. After treatment with interleukin-1β for 24 h, the phenylephrine-induced contraction was inhibited more strongly. Neither

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-NMMA (100 μM) nor aminoguanidine (100 μM) reversed the inhibition, whereas methylene blue (10 μM) partially reversed the inhibition. After treatment with interleukin-1β for 12 or 24 h, the cyclic GMP content increased but to a level lower than that obtained with a 6-h treatment. The effects of sodium nitroprusside (1 μM) to inhibit the phenylephrine-induced contraction and to increase the cyclic GMP content were markedly suppressed by the 24-h interleukin-1β treatment. In contrast, the 24-h interleukin-1β treatment did not change the ability of 8-bromo-cGMP to relax the phenylephrine-stimulated aorta. Addition of

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-NMMA (1 mM) during the 24 h treatment prevented NO production and preserved the sodium nitroprusside-induced cGMP generation by interleukin-1β. The 24 h interleukin-1β treatment increased the threshold concentration of KCl needed to induce contraction without changing the maximum contraction. In the presence of 25.4 mM KCl or the non-selective K⁺ channel inhibitor, tetraethylammonium, the inhibitory effect of the 24-h interleukin-1β treatment on phenylephrine-induced contraction was restored. These results suggest that interleukin-1β inhibits vascular smooth muscle contraction by a time-dependent, dual mechanism. After a 6-h treatment with interleukin-1β, the NO/cyclic GMP system is activated. After a 24-h interleukin-1β treatment, in contrast, the NO/cyclic GMP system may be desensitized and the contraction of vascular smooth muscle is inhibited by another mechanism, possibly membrane hyperpolarization.     

Chemokine production by human vascular smooth muscle cells: modulation by IL-13

1. The production of chemokines by vascular smooth muscle cells (SMC) is implicated in the pathogenesis of atherosclerosis, although the factors regulating chemokine production by these cells are incompletely characterized.
2. We describe the differential stimulation of interleukin-(IL)-8, monocyte chemoattractant protein (MCP)-1 and regulated on activation normal T-cell expressed and secreted (RANTES) synthesis following treatment of human vascular SMC with IL-1α or tumour necrosis factor α (TNFα). Under basal conditions, cultured SMC release very low amounts of IL-8, MCP-1 and RANTES as assessed by specific ELISA. Concentration-response studies with IL-1α or TNFα revealed that each stimulus induced a similar amount of MCP-1. In contrast approximately three fold more IL-8 was induced by IL-1α than by TNFα whereas significant RANTES production was induced only by TNFα. These findings point to a divergence in the regulation of synthesis of the different chemokines in response to IL-1α or TNFα stimulation.
3. The T-cell derived cytokines IL-10 and IL-13 were also found to have differential effects on chemokine production by SMC. IL-13, but not IL-10, significantly enhanced IL-8 and MCP-1 release in response to IL-1α or TNFα. This increase in chemokine release appeared to be accounted for by increased mRNA expression.
4. These findings provide support for the concept that smooth muscle cells can have an active role in a local immune response via the production of chemokines which can be selectively modulated by T-cell derived cytokines.

     

Interferon gamma and interleukin 10 levels in preimplantation embryo culture media

Purpose The aim of our study is to elucidate whether human oocyteslembryos secrete IFN and/or IL-10 and whether the fertilization process depends on the balance between these cytokines.Methods A total of 142 embryo culture media from 24 patients were collected and the cytokine levels were tested with ELISA.Results IFN and IL-10 were detectable in 40.1% and 29.6% of culture media respectively. The difference of IFN and IL-10 levels in media from fertilized oocytes between day 1 and day 2 are significant (0.46 vs. 1.47 and 34.2 vs. 12.7, respectively). However there was no significant difference between the IFN levels of the media from fertilized and nonfertilized oocytes 0.46 vs. 0.85 at day 1 and 1.47 vs. 1.49 at day 2, as well as IL-10 levels 34.2 vs. 30.9 at day 1 and 12.7 vs. 9.58 at day 2 respectively.Conclusions Human preimplantation embryos secrete the cytokines IFN and IL-10. No effect of these cytokines on fertilization process could be shown.Presented at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995, Vienna, Austria.     

Tumor-associated lymphocytes (TAL) are competent to produce higher levels of cytokines in neoplastic pleural and peritoneal effusions than those found in sera and are able to release into culture higher levels of IL-2 and IL-6 than those released by PBMC

This work was designed to study the proliferative response of tumor-associated lymphocytes (TAL) from neoplastic effusions against autologous tumor cells and the immunophenotype pattern of TAL from neoplastic effusions and that of PBMC of the same patients. We also compared the serum levels of the cytokines interleukin (IL) 1, 2 and 6, tumor necrosis factor- (TNF) and soluble IL-2 receptor (sIL-2R) with those present in neoplastic effusions of the same patients. Moreover, we examined the ability of TAL and peripheral blood mononuclear cells (PBMC) to produce and release the cytokines and sIL-2R and to express membrane CD25 following their stimulation with phytohemagglutinin (PHA) in vitro. Finally, we compared the cytokines/sIL-2R production and membrane CD25 expression by PHA-stimulated PBMC of the patients with neoplastic effusions with a series of 90 cancer patients without neoplastic effusions and 20 normal healthy subjects. Thirteen neoplastic pleural and eight peritoneal effusions were collected from 11 patients with primary lung cancer, 7 with primary epithelial ovarian cancer, 1 with breast cancer, 1 with pleural mesothelioma, and 1 with pancreatic cancer. The proliferative response of TAL from neoplastic effusions against autologous tumor cells was lower than the response to PHA, IL-2, and anti-CD3, but significant. The percentage distribution of CD3⁺ and CD8⁺ lymphocyte subpopulations was higher in peritoneal than in pleural effusions, while the CD16⁺ subset was higher in pleural than in peritoneal effusions. The percentage distribution of CD16⁺ was significantly lower in pleural effusions than in PBMC of patients with pleural effusions. The CD39 antigen was higher on TAL from peritoneal effusions than on PBMC of the same patients. The levels of IL-1 and sIL-2R in peritoneal effusions did not differ from those measured in the sera of the same patients, while the levels of IL-2, IL-6, and TNF were higher in the peritoneal effusions. The levels of IL-2, IL-6, TNF, and sIL-2R, but not IL-1, in pleural effusions were significantly higher than those found in the sera of the same patients. The amounts of IL-2 and IL-6 produced by TAL were generally higher than those released by PBMC. The secretion of cytokines IL-1, IL-2, and sIL2R by PHA-stimulated PBMC was lower, but IL-1 and IL-6 secretion was higher in cancer patients with neoplastic effusions than in either cancer patients without neoplastic effusions or normal subjects. The CD25 expression on PHA-stimulated PBMC derived from cancer patients with neoplastic effusions was in the same range as that of cancer patients without neoplastic effusions and normal subjects. These findings suggest that TAL may be able to produce cytokines and may be amenable to immune manipulation.Abbreviations FITC Fluorescein-isothiocyanate - IL Interleukin - mAb Monoclonal antibody - MHC Major histocompatibility complex - NK Natural killer - PBMC Peripheral blood mononuclear cells - PHA Phytohemagglutinin - TAL Tumor-associated lymphocytes - TIL Tumor-infiltrating lymphocytes - TNF Tumor necrosis factor- - sIL-2R Soluble interleukin-2 receptor     

白细胞介素-1受体拮抗剂对博莱霉素致大鼠肺纤维化模型的影响

目的：探讨白细胞介素１受体拮抗剂（ｉｎｔｅｒｌｅｕｋｉｎ１ｒｅｃｅｐｔｏｒａｎｔａｇｏｎｉｓｔ,ＩＬ１ｒａ）治疗博莱霉素（ｂｌｅｏｍｙｃｉｎ,ＢＬＭ）致大鼠肺纤维化模型的作用机制。方法：利用ＭＴＴ法测定经ＩＬ１ｒａ作用前、后１周时该模型大鼠肺泡巨噬细胞产生肿瘤坏死因子α（ｔｕｍｏｒｎｅｃｒｏｓｉｓｆａｃｔｏｒα,ＴＮＦα）,及其培养上清促肺成纤维细胞增殖能力的变化;利用Ｎｏｒｔｈｅｒｎ杂交测定肺泡巨噬细胞ＴＮＦα、血小板衍化生长因子（ｐｌａｔｅｌｅｔｄｅｒｉｖｅｄｇｒｏｗｔｈｆａｃｔｏｒ,ＰＤＧＦ）ｍＲＮＡ的表达。结果：ＢＬＭ致肺纤维化模型１周时,肺泡巨噬细胞ＴＮＦα的产生及该组细胞上清的促成纤维细胞增殖活性与正常对照组相比均明显增强,而ＩＬ１ｒａ（１０ｍｇ·Ｌ－１）对肺泡巨噬细胞ＴＮＦα的产生及该组细胞上清的促成纤维细胞增殖活性有明显的抑制作用。ＢＬＭ致肺纤维化模型１周时肺泡巨噬细胞ＴＮＦα、ＰＤＧＦｍＲＮＡ的表达较正常对照组增高,而ＩＬ１ｒａ对其表达无明显影响。结论：ＩＬ１ｒａ通过对肺泡巨噬细胞的ＴＮＦα产生及其对成纤维细胞增殖活性的抑制,可能对该模型的肺纤维化起到抑制作用     

抗CD3单抗增强激活骨髓抗白血病效应的研究

目的：为了研究增强ｒＩＬ－ ２ 激活的骨髓细胞（激活骨髓ＡＢＭ）的抗白血病效应。方法：应用抗ＣＤ３ 单抗与ｒＩＬ－ ２ 联合作用体外激活骨髓细胞,采用ＭＴＴ比色分析法测定不同条件下ＡＢＭ杀伤肿瘤细胞活性。结果：ｒＩＬ－ ２、抗ＣＤ３ 单抗＋ ｒＩＬ－ ２ 体外诱导３ ｄ 的ＡＢＭ 杀伤活性分别为５６．４％ ±９．０％ ,６５．８％ ±９．２％ ,两组相比差异显著（Ｐ＜ ０．０１）;体外诱导７ ｄ 细胞增殖倍数分别为３．７,６．０ 倍。结论：在合理的诱导条件下,能够增强ＡＢＭ 的杀伤活性,扩大ＡＢＭ 的增殖效应,从而使有限的骨髓细胞在短期内达到有效的治疗剂量     

Effects of theophylline on plasma levels of interleukin-4, cyclic nucleotides and pulmonary functions in patients with chronic obstructive pulmonary disease

Ｔｈｅｏｐｈｙｌｉｎｅｉｓｏｎｅｏｆｔｈｅｍｏｓｔｗｉｄｅｌｙｕｓｅｄｄｒｕｇｓｉｎｔｒｅａｔｉｎｇｃｈｒｏｎｉｃｏｂｓｔｒｕｃｔｉｖｅｐｕｌｍｏｎａｒｙｄｉｓｅａｓｅ（ＣＯＰＤ）．Ｈｏｗｅｖｅｒ,ｔｈｅｔｒａｄｉｔｉｏｎａｌｔｈｅｏｒｙｔｈａｔｔｈ...     

恶性肿瘤放疗前后血清可溶性白细胞介素2受体含量变化的临床意义

目的　探讨血清可溶性白细胞介素２ 受体（ｓ Ｉ Ｌ２ Ｒ）水平与恶性肿瘤患者的病期及疗效的关系。方法　采用双抗体夹心 Ｅ Ｌ Ｉ Ｓ Ａ 法检测１５９ 例恶性肿瘤患者放疗前后血清ｓ Ｉ Ｌ２ Ｒ 水平。结果　恶性肿瘤患者放疗前血清ｓ Ｉ Ｌ２ Ｒ 水平明显高于正常对照组（ Ｐ＜ ００５）;放疗后血清ｓ Ｉ Ｌ２ Ｒ 水平明显低于放疗前（ Ｐ ＜ ０００１）;晚期患者（Ⅲ＋ Ⅳ期）不论是放疗前或放疗后 ｓ Ｉ Ｌ２ Ｒ 水平均明显高于早期患者（Ⅰ＋ Ⅱ期）（ Ｐ ＜ ００５）;各类恶性肿瘤之间血清ｓ Ｉ Ｌ２ Ｒ 水平无显著性差异（ Ｐ ＞００５）。结论　ｓ Ｉ Ｌ２ Ｒ水平在各种恶性肿瘤中的表达无特异性;检测恶性肿瘤患者ｓ Ｉ Ｌ２ Ｒ 放疗前后水平,是对病情估计和治疗疗效评价的一项参考指标。     

冠心病病人淋巴细胞CR1表达及血清sIL—2R水平的变化

目的探讨冠心病病人外周血淋巴细胞补体Ⅰ型受体（ＣＲ１）表达及血清可溶性白细胞介素－２受体（ｓＩＬ－２Ｒ）浓度的变化。②方法采用淋巴细胞花环试验和酶联免疫吸附法（ＥＬＩＳＡ）,检测了７２例冠心病病人和６３例健康人淋巴细胞ＣＲ１花环率（Ｌ－ＣＲ１Ｒ）及血清ｓＩＬ－２Ｒ浓度变化。③结果冠心病病人Ｌ－ＣＲ１Ｒ明显降低,ｓＩＬ－２Ｒ浓度明显增高,与对照组比较差异有极显著性（ｔ＝６．４１４,７．８０６,Ｐ＜０．００１）。冠心病病人Ｌ－ＣＲ１Ｒ与ｓＩＬ－２Ｒ呈负相关（ｒ＝－０．８１５,Ｐ＜０．００１）。不稳定心绞痛（ＵＡ）、急性心肌梗死（ＡＭＩ）和陈旧性心肌梗死（ＯＭＩ）病人Ｌ－ＣＲ１Ｒ和ｓＩＬ－２Ｒ比较,差异亦具有极显著性（Ｆ＝７．８６０,１１．５７９,ｑ＝６．６２７～１０．５５０,Ｐ＜０．００１）,且以ＡＭＩ病人的变化最明显。④结论外周血淋巴细胞ＣＲ１表达和血清ｓＩＬ－２Ｒ浓度异常与冠心病病情变化有密切关系。