Peripheral blood neutrophil production of interleukin-1 receptor antagonist and interleukin-1β

Journal of Clinical Immunology - The objective of this study was to characterize interleukin-1 receptor antagonist (IL-1ra) and interleukin-1β (IL-1β) production by human peripheral blood...     

Content of Proinflammatory Cytokine in Patients with Clinical Remission of Chronic Herpes Infection during Immunocorrection

The concentrations of cytokines (interleukin-1β, interleukin-6, and interferon-γ) in blood plasma from patients with remission of chronic herpes infection were measured during immunocorrective therapy. Our results indicate that immunocorrection is pathogenetically substantiated and immunologically effective. It was manifested in reduction of inflammation and activation of antiviral protection Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 63–66, 2008     

Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways

Summary: Cytokines mediate key communication pathways essential for regulation of immune responses. Full activation of antigen-responding lymphocytes requires cooperating signals from the tumor necrosis factor (TNF)-related cytokines and their specific receptors. LIGHT, a lymphotoxin-β (LTβ)-related TNF family member, modulates T-cell activation through two receptors, the herpesvirus entry mediator (HVEM) and indirectly through the LT-β receptor. An unexpected finding revealed a non-canonical binding site on HVEM for the immunoglobulin superfamily member, B and T lymphocyte attenuator (BTLA), and an inhibitory signaling protein suppressing T-cell activation. Thus, HVEM can act as a molecular switch between proinflammatory and inhibitory signaling. The non-canonical HVEM–BTLA pathway also acts to counter LTβR signaling that promotes the proliferation of antigen-presenting dendritic cells (DCs) within lymphoid tissue microenvironments. These results indicate LTβ receptor and HVEM–BTLA pathways form an integrated signaling circuit. Targeting these cytokine pathways with specific antagonists (antibody or decoy receptor) can alter lymphocyte differentiation and activation. Alternately, agonists directed at their cell surface receptors can restore homeostasis and potentially reset immune and inflammatory processes, which may be useful in treating autoimmune and infectious diseases and cancer.     

Effects of prostaglandin E2 on Th0-type human T cell clones: modulation of functions of nuclear proteins involved in cytokine production

The effects of prostaglandin E₂ (PGE₂) on cytokine productionand proliferation of the CD4⁺ human helper T cell clone SP-B21were investigated. In cells stimulated with antl-CD3 mAb, PGE₂inhibited cell proliferation and the production of all the cytokinesexamined. Addition of rlL-2 fully restored the prollferatlveresponse and partially restored the production of IL-4 and IL-5,but not that of other cytokines. In contrast, In cells stimulatedwith phorbol myrlstate acetate (PMA)/A23187, PGE₂ enhanced theproduction of IL-4 and IL-5, and only partially inhibited theproduction of other cytokines. Therefore, the effects of PGE₂vary depending on the mode of T cell activation, and the IL-4and IL-5 are regulated differently from other cytokines. Ina mobility shift assay, only the NF-B (p50/p5O) homodlmer wasobserved in a complex formed with the B sequence in unstlmulatedSP-B21 cells. When cells were stimulated with antl-CD3 mAb orPMA/A23187, a complex formation of NF-B (p50/p65) heterodlmerwith the B sequence was induced. Interestingly, PGE₂ or di-butyryl(Bt₂cAMP abolished the binding of NF-B (p50/p65) heterodlmerto the B sequence in cells stimulated with antl-CD3 mAb butnot with PMA/A23187. Our results suggest that the target ofPGE₂ action is a component in the signal transductlon pathwayleading to the activation of protein klnase C. However, theinhibition of the T cell activation signals by PGE₂ is selective.PGE₂ enhanced the complex formation with NF-AT, AP-1 and CLEOsequences when the cells were activated by either anti-CD3 mAbor PMA/A23187 stimulation. It seems therefore that PGE₂, byelevating cAMP levels, interferes with the activation pathwayfor NF-B but not for NF-AT, AP-1 or CLEO binding protein.     

Suppression of human lymphocyte responses to specific and non-specific stimuli in human onchocerciasis.

Characterization of in vitro lymphocyte responsiveness was performed on selected groups of onchocerciasis patients from Sudan and Sierra Leone. These patients manifested a very broad range of clinical signs and showed widely divergent parasite infection intensities. Lymphocyte proliferative responses to soluble Onchocerca volvulus antigen (sAg) were poor in infected persons; mitogen and PPD responses were maintained in the normal range in one group of patients from southwestern Sudan, but were profoundly depressed in a group from N.E. Sudan. Proliferative responses and interferon-gamma (INF-gamma) secretion were very significantly depressed in the presence of live microfilariae of O. volvulus or secretions/excretions (S/E) from microfilariae (mf) or from female, but not male, adult parasites. Lymphocyte responses were maintained near normal when exogenous IL-2 was added to these cultures. The results indicate that O. volvulus infection and its clinical consequences are not consistently associated with systemic deficits in immune responsiveness. However, suppression of lymphocyte reactivity by mf and S/E in vitro suggests that direct parasite intervention in host cell responses could be taking place in vivo, perhaps at the local microenvironment level; mediated by effects on cytokine production.     

Reduced ratio of protective versus proinflammatory cytokine responses to commensal bacteria in HLA-B27 transgenic rats

Germ-free HLA-B27 transgenic (TG) rats do not develop colitis, but colonization with specific pathogen-free (SPF) bacteria induces colitis accompanied by immune activation. To study host-dependent immune responses to commensal caecal bacteria we investigated cytokine profiles in mesenteric lymph node (MLN) cells from HLA-B27 TG versus nontransgenic (non-TG) littermates after in vitro stimulation with caecal bacterial lysates (CBL). Supernatants from CBL-stimulated unseparated T- or B- cell-depleted MLN cells from HLA-B27 TG and non-TG littermates were analysed for IFN-gamma, IL-12, TNF, IL-10 and TGF-beta production. Our results show that unfractionated TG MLN cells stimulated with CBL produced more IFN-gamma, IL-12 and TNF than did non-TG MLN cells. In contrast, CBL-stimulated non-TG MLN cells produced more IL-10 and TGF-beta. T cell depletion abolished IFN-gamma and decreased IL-12 production, but did not affect IL-10 and TGF-beta production. Conversely, neither IL-10 nor TGF-beta was produced in cultures of B cell-depleted MLN. In addition, CD4(+) T cells enriched from MLN of HLA-B27 TG but not from non-TG rats produced IFN-gamma when cocultured with CBL-pulsed antigen presenting cells from non-TG rats. Interestingly, IL-10 and TGF-beta, but not IFN-gamma, IL-12 and TNF were produced by MLN cells from germ-free TG rats. These results indicate that the colitis that develops in SPF HLA-B27 TG rats is accompanied by activation of IFN-gamma-producing CD4(+) T cells that respond to commensal bacteria. However, B cell cytokine production in response to components of commensal intestinal microorganisms occurs in the absence of intestinal inflammation.     

IL-1α及与IL-11、LIF和GDNF联合诱导胚鼠皮质、中脑神经干细胞向多巴胺神经元分化的比较

为比较皮质和中脑来源的神经干细胞(NSCs)定向分化为多巴胺神经元的情况,应用无血清和单克隆培养技术,分别从皮质和中脑组织中分离克隆、扩增NSCs,然后分成3组诱导分化:①对照组用10%胎牛血清诱导分化;②IL-1α组在10%胎牛血清的基础上加IL-1α诱导分化;③联合因子组在10%胎牛血清的基础上加IL-1α、IL-11、LIF及GDNF进行诱导分化。用酪氨酸羟化酶(TH)免疫组化染色检测多巴胺神经元。在100倍镜下随机取5个视野,计数每个视野中的TH阳性神经元数;并用图像分析软件处理TH阳性神经元的胞体面积和细胞周长;用STATA7.0统计软件进行统计处理。结果显示,皮质对照组中仅见极少的TH阳性神经元(0.25±0.163),中脑对照组中见少量TH阳性神经元(2±0.378);而皮质IL-1α组有较多的TH阳性神经元(15.5±0.866),中脑IL-1α组中的TH阳性神经元则为皮质IL-1α组的150%(22.875±1.517);皮质联合因子组中的TH阳性神经元数(25.75±0.940)与中脑联合因子组中的TH阳性神经元数(28.875±2.125)接近,无显著差异。胞体面积和细胞周长的结果显示出IL-1α组和联合因子组大于对照组、而联合因子组又优于IL-1α组的趋势。上述结果提示,中脑来源的NSCs本身具有一定的分化为多巴胺神经元的区域特异性,而皮质来源的NSCs在IL-1α、IL-11、LIF及GDNF等细胞因子的诱导下可改变其区域特异性而分化为较多较为成熟的多巴胺神经元。     

Lp(a) lipoprotein is a major risk factor for cardiovascular disease: pathogenic mechanisms and clinical significance

The results of two previous and two recent studies of middle-aged males and females are presented to exemplify the clinical importance of lipoprotein (a) (Lp(a)) as a risk factor for atherosclerosis and coronary heart disease. In these studies various conventional and recently suggested risk factors were included and different methods for Lp(a) quantification were used. Lp(a) was a significant risk factor in all four studies. In the recent prospective case-control study, Lp(a) and cholesterol were found to act synergistically and predict primary acute myocardial infarction in Swedish males. A cholesterol level above 6.5 mmol/1 increased the risk of acute myocardial infarction if the Lp(a) level was above 200 mg/1. The plasma apo A-I level was a protective factor. In the other recent case-control study, an Lp(a) level above 500 mg/1 was a highly significant risk factor in Black and White US women with myocardial infarction or advanced coronary artery disease in addition to low density lipoprotein cholesterol levels above 130 mg/dl. A high apo A-I level was a protective factor. In these studies no other factors tested reached significance in multivariate logistic regression analysis. A hypothetical association between high Lp(a) levels and intracellular infection with Chlamydia pneumoniae is discussed. The results suggest that the Lp(a) level is useful in identifying high-risk individuals. Lowering low density lipoprotein cholesterol below 100 mg/dl (7lt;2.6 mmol/1) seems to be most important in both males and females with high-risk Lp(a) levels.     

Recombinant gp120 induces IL-10 in resting peripheral blood mononuclear cells; correlation with the induction of other cytokines.

Immunological abnormalities present in HIV-1-infected individuals often reflect an imbalance of cytokine production. The HIV-1 gp120 has the ability to induce a number of cytokines, and to enhance immunoglobulin release by normal peripheral blood mononuclear cells (PBMC) in vitro, in the absence of IL-2 production and of lymphoproliferation. This study provides evidence that gp120 is a potent IL-10 inducer in normal PBMC cultures. The pattern of other cytokines induced by gp120 includes interferon-alpha (IFN-alpha) and IFN-gamma, tumour necrosis factor-alpha (TNF-alpha), IL-6, IL-1 alpha and -beta, and not IL-2 and IL-4. These findings further define the pattern of cytokine release induced by gp120 on human resting PBMC. Furthermore, the present findings roughly parallel those observed both in the sera of patients and in the mononuclear cells from HIV+ individuals early after infection, suggesting that gp120 could be a good candidate as one of the agents responsible for cytokine dysregulation observed in HIV-1-infected individuals.     

精神分裂症致炎性细胞因子、酪氨酸羟化酶基因表达水平与临床症状的关系

目的检测精神分裂症患者致炎性细胞因子(白介素-1β、肿瘤坏死因子-α)和酪氨酸羟化酶(TH)的基因表达水平,探讨其与临床症状的关系。方法采用送转录-聚合酶链式反应(RT-PCR)和半定量技术,分别检测39例精神分裂症患者,25例同胞对照和30例正常对照外周血单个核细胞IL-1β、TNF-α和TH的基因表达水平,同时应用PANSS量表评定精神分裂症患者临床症状。结果IL-1β在病例组、同胞对照组和正常对照组的基因表达水平分别为1.52±1.01、1.18±0.99和0.55±0.33;TNF-α在三组样本的基因表达水平分别为1.52±1.09、1.01±0.87和0.61±0.32;TH在三组样本的基因表达水平分别为0.74±0.38、0.70±0.29和0.28±0.20。其中病例组与同胞对照组IL-1β、TNF-α、TH基因表达水平无显著差异(P>0.05);病例组和同胞对照组的IL-1β、TNF-α、TH基因表达水平均显著高于正常对照组(P<0.05或P<0.01)。同时发现IL-1β(r=0.420)、TNF-α(r=0.430)基因表达水平与PANSS量表的一般病理症状分显著相关(P<0.01)。结论精神分裂症患者存在多巴胺功能亢进和致炎性细胞因子的过度表达,且可能受遗传背景影响。致炎性细胞因子可能参与精神分裂症一般病理症状的形成。