Negative regulators of the interleukin-1 system: receptor antagonists and a decoy receptor

The IL-1 system includes 2 agonists, α and β, processing and transport molecules, receptor antagonists, signalling receptor, a decoy receptor and an accessory molecule. Negative pathways of regulation include the antagonists, of which 3 isoforms have been cloned and the type II “decoy” receptor. Molecules that regulate inflammation and immunity coordinatively affect different components of the system. The complexity of the system and the existence of unique pathways of negative regulation, the antagonists and the decoy receptor, emphasize the need for a tight control of the production and action of IL-1.     

The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial

Objective  To determine if statin therapy reduces the incidence of severe sepsis and the levels of inflammatory cytokines in patients with acute bacterial infection. Design  Double-blind placebo controlled randomized clinical trial. Setting  Department of medicine and medical intensive care unit in a tertiary university medical center. Patients and participants  A total of 83 patients with suspected or documented bacterial infection were enrolled. We randomly assigned 42 patients to receive 40 mg of simvastatin orally, followed by 20 mg of simvastatin, and 41 to receive matching placebo. Measurements and results  The study was prematurely terminated due to slow recruitment rate. Here we report the analysis of the secondary outcome: change in cytokines levels at 72 h. Both groups were evenly matched in terms of co-morbidity and severity of illness on admission. Four of the 83 patients enrolled developed severe sepsis, two in each group. No difference was observed in other clinical variables and there were no mortalities. Cytokine levels were randomly assessed in 40 patients (20 in each group). Both TNF-α and IL-6 levels were significantly reduced in the simvastatin group (p = 0.02 and p = 0.02, respectively), while no such difference was observed in the placebo group (p = 0.35 and 0.39, respectively). Conclusions  Statin therapy may be associated with a reduction in the levels of inflammatory cytokines in patients with acute bacterial infections. Large controlled trials will determine if this reduction will translate into a clinical benefit. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

白细胞介素-10及其受体在系统性红斑狼疮中的研究进展

系统性红斑狼疮是一种典型的自身免疫性疾病,其主要免疫学特征是机体发生异常的免疫应答,以T、B淋巴细胞的异常活化最为突出,导致患者体内产生多种自身抗体而造成多器官系统损害,而细胞因子的异常是参与这一发病过程的重要因素之一,尤其白细胞介素(IL)对系统性红斑狼疮的研究较多,本文将IL-10及其在系统性红斑狼疮中的研究进展进行综述。     

Localisation and modulation of prostanoid receptors EP1 and EP4 in the rat chronic constriction injury model of neuropathic pain.

Immunohistochemistry was used to examine the expression of prostaglandin E(2) receptors EP1 and EP4 in sciatic nerves from the rat chronic constriction injury (CCI) model of neuropathic pain. At 21 days post-surgery the CCI rats had developed mechanical hyperalgesia on the operated side, and quantitative image analysis showed a highly significant doubling of the area occupied by EP1- and EP4-positive pixels in sections from CCI nerves when compared to sham-operated controls. Co-localisation studies with the marker ED1 revealed that 73% of the EP1-positive cells and 54% of the EP4-positive cells in the injured nerves represented infiltrating macrophages. Cells negative for ED1 and positive for either EP1 or EP4 were characterised as Schwann cells from their morphology and expression of myelin basic protein and S100 antigens. Similar EP1- and EP4-positive Schwann cell profiles were observed in sections of uninjured control nerves. Low levels of EP receptor expression were found in neurofilament-immunostained axons, but no consistent differences were observed in the levels of axonal EP staining between CCI and control tissue. These data provide further evidence of the importance of prostaglandins in the pathogenesis of neuropathic pain, and suggest that not only infiltrating macrophages but also Schwann cells may be involved in the modulation of these mediators in response to nerve injury.     

Differential effect of benzydamine on pro- versus anti-inflammatory cytokine production: lack of inhibition of interleukin-10 and interleukin-1 receptor antagonist

The production and action of primary proinflammatory cytokines are strictly controlled by a series of circuits to avoid damage that they can cause if produced in excess. Interleukin-10 and interleukin-1 receptor antagonist contribute to the control of the magnitude of the inflammatory responses in vivo. Benzydamine, a non-steroidal anti-inflammatory drug that has been shown to have suppressive activity for the proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, was investigated for its effects on interleukin-10 and interleukin-1ra production. The drug did not modify the production of interleukin-10 and interleukin-1ra by peripheral blood mononuclear cells stimulated with lipopolysaccharide, under conditions where tumor necrosis factor-alpha and interleukin-1beta were decreased. The antiinflammatory capacity of benzydamine might thus result from its ability to reduce the production of proinflammatory cytokines, without affecting antiinflammatory factors.     

A Taql polymorphism in the human interleukin-1β (IL-1β) gene correlates with IL-1β secretion in vitro

In the present study we searched for restriction fragment length polymorphisms (RFLP) in the human interleukin-1 beta (IL-1 beta) gene and for correlations to monocyte (Mo) function in non-related healthy donors and insulin-dependent diabetic patients. We demonstrated a diallelic polymorphism with the restriction enzyme TaqI consisting of fragments of 9.4 kb and 13.4 kb. No differences in allele or genotype frequencies of this RFLP were observed between randomly selected controls and randomly selected patients with insulin-dependent diabetes mellitus (IDDM). However, when analysing IDDM patients negative for HLA-DR3 and -DR4, our data demonstrate that the 13.4 kb allele is more frequent in this group compared to a matched control group. The functional impact of this RFLP was studied by analysing in vitro stimulated Mo IL-1 beta response. An IL-1 beta allele dosage effect on secretory capacity was observed after LPS-stimulation: 13.4/13.4 kb homozygous individuals secreted significantly more IL-1 beta than 9.4/13.4 kb heterozygous individuals, who secreted significantly more than 9.4/9.4 kb homozygous individuals. Analyses of supernatants from LPS-stimulated Mo cultures from individuals with each TaqI IL-1 beta genotype revealed no differences in the mouse thymocyte co-stimulatory assay when compared on a molar basis, indicating that the TaqI polymorphism gave rise only to quantitative differences in expression levels and probably not to a mutant IL-1 beta.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of curcuminoids on inflammatory status in patients with non-alcoholic fatty liver disease: A randomized controlled trial

BackgroundNonalcoholic fatty liver diseases (NAFLD) is a highly prevalent disease that is closely associated with several cardiometabolic complications. The potential anti-inflammatory role of curcuminoids that have already been reported to reduce hepatic steatosis, in patients with NAFLD was explored in this study.MethodsThis double-blind, randomized placebo-controlled trial was conducted for a period of 8 weeks in patients with NAFLD. Subjects (n = 55) were randomly allocated to receive either curcuminoids or placebo. The curcuminoids group received one capsule containing 500 mg curcuminoids (plus 5 mg piperine to increase intestinal absorption) per day for 8 weeks and the control group received matched placebo capsules for the same period. Liver ultrasonography was performed to assess the severity of hepatic steatosis at baseline and the study end. Serum levels of cytokines including interleukin-1α, interleukin-1β, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, interferon γ, vascular endothelial growth factor and epidermal growth factor were measured before and after the intervention.ResultsThe two groups were comparable in demographic features at baseline. The results showed that supplementation with curcuminoids could decrease weight compared to the placebo group (p = 0.016) in patients with NAFLD. Curcuminoids supplementation improved the severity of NAFLD according to the ultrasound results (p = 0.002). Moreover, serum concentrations of TNF-α (p = 0.024), MCP-1 (p = 0.008) and EGF (p = 0.0001) were improved by curcuminoids in NAFLD patients.ConclusionsThe results of our study showed that curcumin supplementation can improve serum levels of inflammatory cytokines in subjects with NAFLD and this might be at least partly responsible for the anti-steatotic effects of curcuminoids.     

Platelets in ulcerative colitis and Crohn's disease express functional interleukin-1 and interleukin-8 receptors

Abstract Tissue and plasma concentrations of several cytokines are increased in patients with inflammatory bowel disease (IBD). Platelets play an important role in inflammation and circulate in an activated state in patients with IBD. This study assesses the expression of IL-8 and IL-1 receptors on the surface of platelets from patients with IBD using phycoerythrin (PE)-labelled recombinant human rhIL-1 β and rhIL-8 and flow cytometry. The percentage IL-1R expressing platelets (median and interquartile range IQR) in the IBD group was 8·7% (5·5–18·2) compared to 4·2% (2·3–6·1) in controls ( P = 0·02). The percentage IL-8R expressing platelets in the IBD group was 22·5% (16·5–27·9) and 9·2% (4·3–9·6) in controls ( P < 0·001). Furthermore, platelet IL-1R expression in patients with IBD was inversely related to the total daily dose of steroids ( r =–0·71, P < 0·01 linear regression analysis). Finally, platelet rich plasma from healthy controls was stimulated with rhIL-1 β and rhIL-8 and assessed for activation dependent expression of platelet aGPIIb/IIIa and CD62 (p-selectin, GMP-140). IL-1 β and IL-8 in vitro significantly and specifically activated the platelets. The surface membrane of platelets is able to express functional IL-1R and IL-8R, the expression of which is signficantly increased in IBD. Interleukin-1 β and IL-8 modulate platelet activation in vitro indicating a target role for platelet function in inflammation.     

云南地区白细胞介素1基因型分布与幽门螺杆菌感染的关系

目的 探讨云南地区白细胞介素1（IL-1）基因型分布特点及其与幽门螺杆菌（Hp）感染、定植密度间的关系。方法 对符合研究标准的患者，进行Hp感染及Hp定植密度的评定；用PCR—RFLP检测外周血的IL-1B^-511、IL-1B^＋3954、IL-1RN的基因型。结果 IL-1B^-511基因型中，C／C24例（17．3％）、C／T75例（54．0％）、T／T40例（28．8％）；IL-1B^＋3954。基因型中，C／C132例（95．0％）、C／T7例（5．0％）、无T／T；IL-1RN位点L／L与1／2基因型各占111例（79．9％）、27例（19．4％）、2／2基因型1例。IL-1B^-511含T基因型是DU患者Hp感染的易感因素，OR为6．1。在≥60岁亚组中，IL-1B^-511含T基因型是Hp定植密度程度的危险因素，OR为8．0。结论 东西方非胃肿瘤患者人群IL-1基因型分布存在差异，为研究东西方人群Hp感染相关临床结局类型差异的原因提供线索。IL-1B^-511含T基因型与DU患者Hp感染率高及与易形成重度Hp感染相关。     

白细胞介素-27研究进展

细胞因子介导的免疫反应在许多疾病的发病机制中均发挥着关键性作用。白细胞介素-27（IL-27）是近期新发现的隶属于IL-6/IL-12家族的细胞因子,它通过不同的作用机制参与自身免疫性疾病、炎症及肿瘤等多种疾病的发生、发展及转归。许多研究证明,在缺乏IL-27的免疫疾病中,多种炎症因子高表达,从而产生严重的炎症反应。然而,IL-27还能促进Th1细胞的分化,具有一定的促炎作用。因此,IL-27具有免疫抑制和促炎双重作用。本文主要从IL-27在自身免疫性疾病、感染和肿瘤等疾病中发挥的作用及近期研究进展方面加以阐述。     

Insulin receptors in acute and chronic lymphoid leukaemias

Abstract. Normal lymphocytes lack insulin receptors. The binding of this hormone was studied in twelve patients with acute lymphoblastic leukaemia (ALL) and fourteen patients with chronic lymphocytic leukaemia (CLL). Lymphoblasts from ALL have been found to possess hormone receptors with properties identical to those of the known target cells for insulin: specificity, pH and temperature dependence, and ligand-induced increase in dissociation rate. All patients with ALL displayed insulin receptors on their lymphoblasts. The null-type cells possessed higher numbers of binding sites than the T-type cells, without overlapping of the values. In the fourteen patients with CLL, eight had low levels of insulin receptors on their lymphocytes while six showed a complete lack of such binding sites. Our results suggest that measurement of insulin binding might be a useful non-immunological marker for the classification of human leukaemias.     

Elevated production of inflammatory mediators including nociceptive chemokines in patients with neck pain: a cross-sectional evaluation

Objective

This study investigated whether the production of inflammatory mediators and chemotactic cytokines (chemokines) is altered in patients with chronic and recurrent neck pain (NP).

Methods

Cross-sectional data evaluating blood and serum samples were obtained from 27 NP patients and 13 asymptomatic (control) subjects recruited from a chiropractic outpatient clinic. Cell cultures were activated by lipopolysaccharide (LPS) and phytoheamagglutinin for 24 to 48 hours. The levels of tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1, also known as CCL2 (CCL2/MCP-1), and macrophage inflammatory protein 1α or CCL3 (CCL3/MIP-1α) were determined by specific immunoassays. Serum levels of nitric oxide metabolites were evaluated simultaneously, in vanadium III-reduced samples, by Griess reaction.

Results

Low levels of constitutive (spontaneous) TNF-α production were present in 7 of the 27 cultures from patients with NP. Both LPS-induced TNF-α production and inducer (LPS/phytoheamagglutin)-stimulated production of CCL2 were significantly elevated (P = .00) in patients compared with controls. In patients, the constitutive synthesis of CCL3 occurred significantly more frequently (P = .00) and ranged from 30 to more than 2000 pg/mL. Finally, serum levels of nitric oxide were significantly elevated (P = .00) in NP patients.

Conclusions

Production of inflammatory mediators was consistently elevated in NP patients in this study, both in vitro and in vivo, and activation of inflammatory pathways was accompanied by up-regulation of CC chemokine synthesis. This suggests that, in NP patients, CC chemokines may be involved in regulation of local inflammatory response through recruitment of immune cells to the inflamed tissue and exert pronociceptive effects.     

In-vitro anti-inflammatory and immunomodulatory effects of grepafloxacin in zymogen A- or Staphylococcus aureus -stimulated human THP-1 monocytes

 The effects of grepafloxacin on the release of cytokines, chemical mediators, hydrolytic enzyme activities, and lipoxygenation in zymogen A- or Staphylococcus aureus-stimulated human THP-1 monocytes were evaluated. Initially, consistent with stimulation of phagocytic mechanisms of the monocytes, increases in cyclic adenosine monophosphate (cAMP) release, nitric oxide [NO] release, and hydrogen peroxide [H₂O₂] release, with a small decrease in cellular pH, occurred within 2 h. Enzymatic activities associated with oxygen burst of phagocytic cells (e.g., protein kinase C and nicotinamide adenine dinucleotide phosphate, reduced (NADPH) oxidase) were elevated, suggesting that monocytes attempted to destroy the invading organism through an innate phagocytic cidal immunologic mechanism. After 1–2 h of exposure to grepafloxacin, the oxygen burst and the release of proinflammatory cytokines and chemical mediators were suppressed. After 4 h, suppression of n-acetyl glucosaminidase (NAG) and cathepsin D activities and lipid peroxidation occurred, suppressing the pathogen-induced spread of infection and inflammation. Release of tumor necrosis factor (TNFα), interleukin (IL)-1, IL-6, and IL-8 was inhibited by grepafloxacin in a concentration-dependent manner, suggesting a reduction in the acute-phase inflammatory responses initiated by cytokine release from monocytes. Later, S. aureus were killed through inhibition of DNA synthesis, consistent with a bacteriostatic effect. Drug action against invading organisms appears to occur through multiple processes. Modulation of the innate immune system occurs within the first hour, causing the activation of cytokines, chemical mediators, and hydrolytic enzymes. A second phase between 2–4 h appears to involve the suppression of cellular components involved in inflammation and the spread of the infection. The third response, an apparent bacteriostatic inhibition of DNA synthesis, causes bacterial death. Received: August 22, 2002 / Accepted: January 13, 2003 Acknowledgments We would like to thank Otsuka Pharmaceuticals for the donation of active drug powder.     

Endothelium-derived vasoactive agents, AT1 receptors and inflammation

Angiotensin II, through activation of the angiotensin II-type 1 receptor, induces generation of inflammatory mediators in the blood vessel wall and as such plays an active role in the inflammation process. Direct stimulation of reactive oxygen species and nuclear factors seem to be key mechanisms through which this receptor induces inflammation. Inflammatory molecules are also known to modify endothelial cell function, especially endothelium-derived vasoactive agents, and inflammation is increasingly recognized as primary cause of major vascular disorders. There is accumulating evidence that stimulation of the type 1 angiotensin II receptor participates in vascular dysfunction by reducing activity of the endothelium-derived relaxants nitric oxide and hyperpolarizing factors. Furthermore activation of this angiotensin II receptor also enhances generation of endothelium-derived constricting factors, such as endothelin-1. This change in endothelial cell output not only impairs blood vessel relaxation but leads to pro-inflammatory and pro-coagulation conditions that are associated with disease initiation and progression. Pharmacological inhibitors of the angiotensin II pathway and the type 1 receptor subtype are in current clinical use for the treatment of hypertension. However evidence supports that these agents have a positive therapeutic benefit in other vascular pathologies with recognized inflammatory etiology, such as atherosclerosis.     

白细胞介素4受体α链S786P的基因多态性

目的:检测中国汉族人群中是否存在白细胞介素4受体α链基因上S786P位点的多态性,并测定其在正常体检者和支气管哮喘患者中的基因频率和基因型频率的分布,判断它的多态性是否与支气管哮喘高度相关。方法:提取外周血白细胞的基因组DNA作为模板。通过PCR-RFLP对S786P位点多态性进行检测;计算基因频率和基因型频率并分析其与支气管哮喘的相关性。结果:在165例中国人中没有发现S786P的多态性,只存在S786,没有检测到S786/P786杂合子和P786/P786的纯合子。发现中国人群中不存在这个位点的多态性。结论:白细胞介素4受体α基因S786P在中国人群中不存在多态性,表明中国人群不适合作S786P多态性与支气管哮喘相关性的研究。     

Human prostate cancer cells induce inflammatory cytokine secretion by peripheral blood mononuclear cells

A substantial number of studies provide evidence that inflammation may play a significant role in the pathogenesis of prostate cancer via increased activity of inflammatory cytokines, particularly IL-6. We have previously shown that peripheral blood mononuclear cells (PBMC) are capable of carrying out an in vitro “immunomodulatory dialog” with colon cancer cells expressed by an increased production of pro-inflammatory cytokines by PBMC. The aim of the current study was to examine the model of cell-to-cell interaction between PBMC and prostate cancer cells from two lines – androgen resistant (PC-3) and androgen-dependent (LNCaP). For that purpose, cancer cells from both lines were incubated with PBMC, and cytokine secretion by PBMC was evaluated. The results showed a cell-concentration dependent increase in secretion of the pro-inflammatory cytokine IL-6 by PBMC induced by cells from both lines, whereas generation of IL-1β and the anti-inflammatory cytokine IL-10 were found to be increased after incubation with PC-3 cells only. The secretion of IL-10 was slightly lower following incubation of PBMC with supernatants derived from PC-3 cells. The results of the study support the possibility that prostate cancer cell-induced cytokine production by PBMC, and particularly IL-6, are involved in prostate cancer development. The discrepancy between the effect of the two prostate cancer cell lines on cytokine secretion by PBMC may be due to their different androgen dependency.     

Role of the equilibrium between colon cancer and mononuclear cells in cytokine production

Patients with ulcerative colitis and Crohn's disease are at increased risk for colorectal cancer, a phenomenon assumed to be at least in part consequence of chronic inflammation. The purpose of this study was to examine whether human colon cancer cells may promote immune cells to produce cytokines, particularly those involved in inflammatory reaction. HT-29 and RKO human colon cancer cell lines were used. Human peripheral blood mononuclear cells (PBMC) were incubated for 24 h without or with cancer cells, or with supernatants derived from these cells cultured at the same conditions. TNFα, IL-1β, IL-6, IFNγ, IL-1ra and IL-10 secreted by PBMC were detected using specific ELISA kits. Interaction between colon cancer cells and PBMC induced secretion of pro- and anti-inflammatory cytokines in a dose-dependent manner. Furthermore, supernatants from increasing number of colon cancer cells caused a dose-dependent cytokine secretion. However, the production of cytokines was more pronounced when PBMC were directly exposed to tumor cells as compared to their supernatants. The results of our experimental model demonstrating an altered balance between pro- and anti-inflammatory cytokines generated by interaction between colon cancer and immune cells support the role of the malignant cells in promoting inflammation as one of the mechanisms for progression of colon cancer.     

白介素6与冠状病毒肺炎关系的研究进展

目前已知感染人的冠状病毒共有7种,其中HCoV-OC43、HCoV-229E、HCoV-NL63、HCoV-HKU1感染常常仅表现出轻度急性上呼吸道感染症状;SARS-CoV、MERS-CoV以及2019-nCoV可能引起较为严重的病症。冠状病毒感染可使机体产生细胞因子风暴,这是导致急性呼吸窘迫综合征的重要原因。目前对白介素6的研究相对成熟。本文就白介素6与冠状病毒感染的研究进展做一综述。