Interleukin-18: Biological properties and role in disease pathogenesis

Initially described as an interferon (IFN)γ-inducing factor, interleukin (IL)-18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL-17-producing γδ T cells and macrophage activation. IL-18, a member of the IL-1 family, is similar to IL-1β for being processed by caspase 1 to an 18 kDa-biologically active mature form. IL-18 binds to its specific receptor (IL-18Rα, also known as IL-1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL-18Rβ chain. IL-18 then uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL-18 also binds to the circulating high affinity IL-18 binding protein (BP), such as only unbound free IL-18 is active. IL-18Rα may also bind IL-37, another member of the IL-1 family, but in association with the negative signaling chain termed IL-1R8, which transduces an anti-inflammatory signal. IL-18BP also binds IL-37 and this acts as a sink for the anti-inflammatory properties of IL-37. There is now ample evidence for a role of IL-18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL-18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain-of-function mutations, IL-18 circulates in the range of tens of nanograms/mL. HS is treated with the IL-1 Receptor antagonist (anakinra) but also specifically with IL-18BP. Systemic juvenile idiopathic arthritis or adult-onset Still's disease are also characterized by high serum IL-18 concentrations and are treated by IL-18BP.     

大鼠胰岛β细胞损伤中IL-18的作用研究

新生Wistar大鼠离体胰岛与细胞因子孵育后 ,观测胰岛素释放和一氧化氮 (NO )生成的变化 ,并用逆转录 聚合酶链反应 (RT PCR )观察IL 18受体信号链 (IL 18Rβ )mRNA的表达水平。结果表明 :(1) 0 6 2 5～ 10nmol/L基因重组小鼠 (rm )IL 18孵育胰岛 2 4h后 ,对累积的和葡萄糖刺激的胰岛素释放以及NO生成均无显著效应 ;(2 ) 2 0 0U/ml基因重组大鼠 (rr)γ干扰素 (IFN γ )或 2 5 0U/ml基因重组人 (rh )肿瘤坏死因子 α (TNF α)单独存在对胰岛素释放和NO生成均无明显效应 ,也不能促使 10nmol/LrmIL 18对胰岛素释放和NO生成产生影响 ;(3) 2 0 0U/mlrrIFN γ +2 5 0U/mlrhTNF α或 15pg/mlrhIL 1β均明显促进NO生成和抑制胰岛素释放 ,而 10nmol/LrmIL 18则不影响IFN γ +TNF α或IL 1β的上述效应 ;(4 )即使经IL 1β和 (或 )IFN γ +TNF α或IL 12孵育后 ,大鼠胰岛素瘤 (RIN )细胞或离体大鼠胰岛仍未见IL 18RβmRNA的表达。提示IL 18在细胞因子所致胰岛β细胞损伤中不发挥直接作用 ,原因是IL 18受体在胰岛 β细胞中不表达。     

Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-gamma, IL-4, IL-10 and IL-13) in patients with allergic asthma

Allergen-reactive T helper type-2 (Th2) cells and proinflammatory cytokines have been suggested to play an important role in the induction and maintenance of the inflammatory cascade in allergic asthma. We compared the plasma concentrations of novel proinflammatory cytokines IL-17 and IL-18, other proinflammatory cytokines IL-6 and IL-12, Th2 cytokines IL-10 and IL-13, and intracellular interferon-gamma (IFN-gamma) and IL-4 in Th cells of 41 allergic asthmatics and 30 sex- and age-matched health control subjects. Plasma cytokines were measured by enzyme-linked immunosorbent assay. Intracellular cytokines were quantified by flow cytometry. Plasma IL-18, IL-12, IL-10, IL-13 concentrations were significantly higher in allergic asthmatic patients than normal control subjects (IL-18: median 228.35 versus 138.72 pg/ml, P < 0.001; IL-12: 0.00 versus 0.00 pg/ml, P = 0.001; IL-10: 2.51 versus 0.05 pg/ml, P < 0.034; IL-13: 119.38 versus 17.89 pg/ml, P < 0.001). Allergic asthmatic patients showed higher plasma IL-17 and IL-6 concentrations than normal controls (22.40 versus 11.86 pg/ml and 3.42 versus 0.61 pg/ml, respectively), although the differences were not statistically significant (P = 0.077 and 0.053, respectively). The percentage of IFN-gamma-producing Th cells was significantly higher in normal control subjects than asthmatic patients (23.46 versus 5.72%, P < 0.001) but the percentage of IL-4 producing Th cells did not differ (0.72 versus 0.79%, P > 0.05). Consequently, the Th1/Th2 cell ratio was significantly higher in normal subjects than asthmatic patients (29.6 versus 8.38%, P < 0.001). We propose that allergic asthma is characterized by an elevation of both proinflammatory and Th2 cytokines. The significantly lower ratio of Th1/Th2 cells confirms a predominance of Th2 cells response in allergic asthma.     

Role of IL-18 in the secretion of Il-1beta, sIL-1RII, and IL-1Ra by human neutrophils

In the present study we investigated the effect of IL-18 on the production of IL-1β, IL-1Ra and sIL-1RII by human neutrophils. Our observations indicate that rhIL-18 induces IL-1β and, to a lesser extend, IL-1Ra and sIL-1RII production by human neutrophils isolated form peripheral blood. However, this effect was less important in comparison with LPS-stimulation. Moreover, the results obtained suggest that IL-18 can induce priming of neutrophils for IL-1β and, to a lesser extend, IL-1Ra and sIL-1RII production by LPS-stimulated cells. The capacity of IL-18 to serve as an effective modulator for IL-1β and its regulatory proteins may have significance in the inflammatory and immune reactions mediated by IL-1β.     

慢性肾病患者细胞因子测定的临床意义

目的：探讨了慢性肾病患者血清IL-6、IL-8、IL-10和IL-18水平的变化及意义。方法：分别应用放射免疫分析和酶联法对32例慢性肾病患者进行了血清IL-6、IL-8、IL-10和IL-18测定,并与35名正常健康人作比较。结果：慢性肾病患者血清IL-6、IL-8、IL-10和IL-18水平显著地高于正常人组（P〈0.01）,经治疗6个月后与正常人组比较仍有差异（P〈0.05）。结论：检测慢性肾病患者血清IL-6、IL-8、IL-10和IL-18水平的变化对疾病的预后观察具有重要的临床价值。     

多发性骨髓瘤患者血清IL-18和sVCAM-1的水平及临床意义

目的探讨多发性骨髓瘤患者血清白细胞介素18（IL-18）和可溶性血管细胞黏附分子-1（sVCAM-1）的水平及临床意义。方法应用ELISA法检查15例多发性骨髓瘤患者治疗前的血清IL-18和sVCAM-1的水平,并与正常对照进行比较。结果多发性骨髓瘤患者血清IL-18和sVCAM-1的水平[（1154.6±299）pg/ml和（1704.5±405.86）ng/ml]明显高于正常对照组[（256.39±59）pg/ml和（538.16±91.21）ng/ml]。结论多发性骨髓瘤患者血清IL-18、sVCAM-1含量明显增高,可能与多发性骨髓瘤的发病机制有关。     

丙型肝炎患者血清细胞因子水平与肝功能损伤的相关性探讨

目的：检测血清可溶性L-selectin（L-选择素）、sICAM-1（细胞粘附因子-1）、IL-6（白细胞介素-6）、IL-10（白细胞介素-10）、IL-18（白细胞介素-18）在丙型肝炎病毒感染造成肝功能损害过程中的作用。方法：应用酶联免疫吸附法（ELISA）对62例丙型肝炎患者进行了血清中L-selectia、sICAM-1、IL-6、IL-10、IL-18水平检测及相关的肝功能、生化指标进行相关分析,并与36例正常健康人作比较。结果：丙型肝炎患者血清L-selectin、sICAM-1、IL-6、IL-10、IL-18水平均非常显著地高于正常人组（P〈0．01）,且与ALT（谷丙转氨酶）、TBIL（总胆红素）水平呈明显的正相关。结论：检测丙型肝炎患者血清中L-selectin、sI—CAM-1、IL-6、IL-10、1L-18水平在一定程度上反映了机体的免疫功能状态和肝细胞损伤的程度,具有临床应用价值。     

Epigenetic regulation of epithelial dectin-1 through an IL-33-STAT3 axis in allergic disease

Allergic diseases arise in susceptible individuals in part because of decrements in protective pathways. The mechanism by which these anti-inflammatory molecules become repressed remains unclear. We have previously reported that epithelial dectin-1 prevents aberrant type 2 responses and is downregulated in the epithelium of allergic patients. Here, we report that dectin-1 is constitutively expressed by the respiratory epithelium in humans and that IL-33 specifically acts as a repressor of dectin-1. Mechanistically, this occurs via IL-33-dependent STAT3 activation and the subsequent repression of the dectin-1 gene, CLEC7A. We have identified a novel enhancer region upstream of the proximal promoter of CLEC7A that is only accessible in epithelial cells, but not in hematopoietic cells. Epigenetic repression of CLEC7A through this newly identified locus, downstream of an aberrant IL-33-STAT3 axis, occurs in the epithelium of allergic individuals. Collectively, our data identify a mechanism of epigenetic fine-tuning of dectin-1 expression in epithelial cells that may participate in allergenicity.     

COPD患者血清IL-6、IL-8、hs-CRP和IL-18检测的临床意义

目的：观察慢性阻塞性肺疾病（COPD）患者治疗前后血清IL-6、IL-8、hs-CRP和IL-18水平的变化及临床意义。方法：应用放射免疫分析和免疫比浊法对32例COPD患者进行了治疗前后血清IL-6、IL-8、hs-CRP和IL-8检测,并与35名正常健康人作比较。结果：COPD患者在治疗前血清IL-6、IL-8、hs-CRP和IL-18水平均非常显著地高于正常人组（P〈0.01）,经中西医结合治疗1个月后与正常人组比较仍有差异（P〈0.05）。结论：IL-6、IL-8、hs-CRP和IL-18的测定,可适用为一种筛选方法,其变化可能以不同的方式参与了COPD的发病,此外,该些项目的检测对了解病情、指导治疗具有重要的临床价值。     

Lipopolysaccharide increased the expression levels of IL-18, ICE and IL-18 R in murine Leydig cells

PROBLEM: This study examined the effect of lipopolysaccharide (LPS) on the capacity of Leydig cells to produce and express interleukin-18 (IL-18), IL-18 receptor (IL-18R) and the IL-1beta-converting enzyme (ICE) (IL-18 family), under in vitro conditions. METHOD OF STUDY: Primary Leydig cells (LCs) were isolated from murine testis by the Percoll technique, and cultured both in the presence and absence of LPS (0.1, 1, 5 microg/mL) for 3 and 24 hr. LCs were examined for their capacity to produce and express IL-18 family molecules by using immunohistochemical staining (IHC), enzyme-linked immunosorbent assay (ELISA), Western blot and real-time polymerase chain reaction (PCR) analysis. RESULTS: Leydig cells were shown to constitutively express IL-18, as examined by IHC, ELISA, Western blot and real-time PCR analysis. Addition of LPS to LC cultures was shown to significantly increase the basal levels of IL-18, in a dose- and time course-dependent manner, as examined by ELISA, Western blot and real-time PCR analysis. In addition, LPS increased LC cultures to express ICE and IL-18 R, as examined by real-time PCR analysis. CONCLUSION: Our results demonstrate that LPS increased the capacity of murine LCs to produce the IL-18 family molecules. IL-18, in the testis, might be involved in the regulation of physiological and infection/inflammatory processes, and thus, could be a component of the autocrine/paracrine factor net that controls steroidogenesis and male fertility; further studies are needed to confirm this possibility.     

类风湿性关节炎患者IL-6、IL-18和CRP的水平变化及意义

目的：研究类风湿性关节炎（RA）患者血清白细胞介素-6（IL-6）、白细胞介素-18（IL-18）和C-反应蛋白（CRP）水平的变化及其临床意义。方法：收集84例RA患者,以70例健康体检者作对照。采用双抗体夹心酶联免疫吸附法测定血清IL-6、IL-18和免疫荧光法测定CRP的水平,并测定血小板计数（Plt）、血沉（ESR）、类风湿因子（RF）。结果：RA患者的血清Plt、ESR、RF、IL-6、IL-18和CRP的含量明显高于健康对照组（P〈0.01）。RA患者活动期上述指标含量（除RF外）均显著高于稳定期（P〈0.01）,Plt升高RA患者组与Plt正常组相比,RF、ESR、IL-6、IL-18和CRP水平均有明显统计学差异（P〈0.05）。结论：IL-6、IL-18和CRP在RA患者的疾病发展过程中发挥着重要作用,它们的水平变化与RA患者病情有关,联合动态监测有助于临床观察RA患者的病情变化和治疗效果。     

Circulating proinflammatory cytokines (IL-1 beta, TNF-alpha, and IL-6) and IL-1 receptor antagonist (IL-1Ra) in fulminant hepatic failure and acute hepatitis.

Fulminant hepatic failure (FHF) is characterized by massive necroinflammation of the liver tissue and is associated with high mortality. Serum concentrations of IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-1 receptor antagonist (IL-1Ra) were measured in 30 patients with FHF and in 23 patients with acute hepatitis (AH) before start of treatment and in 23 healthy controls. Levels of all four molecules were increased significantly in FHF compared with AH, in which values were higher than in the healthy controls. High serum levels of IL-1 beta and a significantly reduced ratio of IL-1Ra to IL-1 beta (IL-1Ra/IL-1 beta) were observed in FHF patients who subsequently died compared with subjects who survived. TNF-alpha and IL-6 concentrations were correlated with levels of human hepatocyte growth factor (hHGF), an index of hepatocyte regeneration. Although serum cytokine levels varied considerably between patients within each group studied, it is suggested that the striking elevation in proinflammatory cytokine levels in FHF may reflect both the insufficiency of hepatitis virus elimination and a failure to control a vicious cytokine cascade leading to overwhelming hepatocyte destruction rather than regeneration. The high cytokine levels observed in these patients and the significantly elevated IL-1Ra/IL-1 beta ratio in FHF patients who survived compared with those who did not suggest the possible therapeutic use of cytokine antagonists for the control of this life-threatening disease.     

牙周病患者血清细胞因子测定的临床意义

目的：探讨了牙周病患者血清IL-8、IL-10、IL-18和M—CSF检测的临床意义。方法：应用放射免疫分析和酶联免疫法对55例牙周病患者进行了治疗前后血清IL-8、IL-10、IL-18和M-CSF水平检测,并与35名正常健康人作比较。结果：牙周病患者在治疗前血清IL-8、IL-10、IL-18和M-CSF水平均非常显著地高于正常人组（P〈0．01）,经治疗后-个月,与正常人组比较仍有显著性差异（P〈0．05）。结论：细胞因子IL-8、几-10、几-18和M-CSF在牙周病的发生、发展过程中相互作用,观察其浓度的变化对探讨其发病机理、预防和指导用药均有重要价值。     

肺炎支原体肺炎患儿治疗前后血清IL-2、IL-10、IL-18和D-D检测的临床意义

目的：探讨了肺炎支原体肺炎患儿治疗前后血清IL-2、IL-10、IL-18和D—D水平的变化及临床意义。方法：应用放免法、酶联法和免疫比浊法对32例肺炎支原体肺炎患儿进行了治疗前后血清IL-2、IL-10、IL．18和D—D检测。并与35名正常健康儿比较。结果：肺炎支原体肺炎患儿在治疗前血清IL-2水平显著地低于正常儿组（P〈0．01）,而IL-10、IL-18和D-D水平又非常显著地高于正常儿组（P〈0．01）,经治疗1个月后则与正常儿组比较无显著性差异（P〉0．05）,且血清IL-2水平与IL．10、IL．18和D-D水平呈显著负相关（r=-0．4806、-0．5014、-0．5988,P〈0．01）。结论：血清IL-2、IL—10、IL-18和D—D参与了肺炎支原体感染的全过程,检测这些细胞因子的变化有助于诊断、治疗和预后,具有-定的临床价值。     

急性结膜炎患者治疗前后血清hs-CRP、IL-6、IL-10、IL-18检测的临床意义

目的:探讨了急性结膜炎患者治疗前后血清hs-CRP、IL-6、IL-10、IL-18水平的变化及意义.方法:分别应用放免法、免疫比浊法和酶联法对38例急性结膜炎患者进行了血清hs-CRP、IL-6、IL-10和IL-18水平检测,并与35名正常健康人作比较.结果:急性结膜炎患者在治疗前血清hs-CRP、IL-6、IL-10和IL-18水平均非常显著地高于正常人(P＜0.01),经2周的抗炎治疗后则与正常人比较无显著性差异(P＞0.05).结论:检测急性结膜炎患者血清hs-CRP、IL-6、IL-10和IL-18水平的变化对临床观察预后有重要的临床价值.     

Special aspects of interleukin-33 and the IL-33 receptor complex

Interleukin-33 (IL-33) is an unconventional member of the IL-1 family: it is a dual function cytokine. Many different cell types, tissue cells and leukocytes, produce IL-33 either constitutively or after stimulation and release it by a poorly defined molecular mechanism. Free IL-33 acts as a classical cytokine by binding to target cells expressing receptors for IL-33 minimally consisting of ST2 and IL-1RAcP. Depending on the target cell type IL-33 will stimulate cell-type specific signal transduction mechanisms and thereby change the biosynthetic profile of the respective cell. In addition, it is stored in the nucleus of cells and may be released after cell stress, death by injury or necrosis, acting as an alarmin by orchestrating a sterile inflammation. Furthermore, IL-33 has intracrine functions in the cell producing it, which are independent of IL-33 receptors. Intracellular IL-33 is predominantly found in the nucleus associated to the chromatin and may exert gene regulatory function by yet poorly defined mechanisms. It is the aim of this review to address two basic biological aspects of the IL-33/IL-33 receptor system. First, to summarize the current understanding of the fate and function of intracellular IL-33, and second, to discuss recent advances in the knowledge of the molecular composition, function and regulation of the IL-33 receptor complex, including initial signaling mechanisms.     

肾病综合征患儿治疗前后血浆leptin、血清IL-6和IL-18水平的变化及临床意义

目的:探讨了肾病综合征患儿治疗前后血浆leptin和血清IL-6、IL-18水平的变化及临床意义.方法:应用放射免疫分析和酶联法对31例肾病综合征患儿进行了治疗前后血浆leptin和血清IL-6、IL-18的检测,并与30名正常健康儿作比较.结果:肾病综合征患儿在治疗前血浆leptin和血清IL-6、IL-18水平均非...     

消化性溃疡患者输注悬浮红细胞前后血清Gas、IL-2、IL-10和IL-18水平的变化及临床价值

目的:探讨了消化性溃疡患者输注悬浮红细胞前后Gas、IL-2、IL-10和IL-18水平的变化及临床意义.方法:应用放射免疫分析和酶联法对31例消化性溃疡患者输注悬浮红细胞前后Gas、IL-2、IL-10和IL-18进行了检测,并与35名正常健康人做比较.结果:消化性溃疡患者在治疗前血清IL-2水平显著低于正常人组(P...     

GM-CSF, IL-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, ICAM-1 and VCAM-1 gene expression and cytokine production in human duodenal fibroblasts stimulated with lipopolysaccharide, IL-1 alpha and TNF-alpha.

The role of mucosal fibroblasts in intestinal inflammatory reactions is not known. In this study, we demonstrate that fibroblasts grown from histologically normal human duodenal biopsy tissues expressed mRNA genes for granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) when stimulated with lipopolysaccharide (LPS) or IL-1 alpha. The increased mRNA expression of GM-CSF, IL-1 alpha, IL-1 beta, IL-6 and IL-8 in response to IL-1 alpha and LPS stimulation was time- and dose-dependent. In contrast, IL-10 was weakly expressed when fibroblasts were stimulated with LPS, IL-1 alpha or tumour necrosis factor-alpha (TNF-alpha), but the expression was enhanced in the presence of cycloheximide combined with optimal concentrations of LPS, IL-1 alpha or TNF-alpha, IL-1 alpha was a more potent stimulator than LPS for GM-CSF, IL-6, IL-8 and IL-10 expression, but not for IL-1 alpha and IL-1 beta. Increased GM-CSF, IL-6 and IL-8 gene expression was associated with the production of cytokine proteins in culture supernatant, but IL-1 alpha and IL-1 beta remained undetectable. Dexamethasone suppressed both gene expression and protein production of GM-CSF, IL-6 and IL-8 when fibroblasts were exposed to IL-1 alpha. TNF-alpha stimulated the release of GM-CSF, IL-6 and IL-8 and, combined with IL-1 alpha, cytokine production was enhanced synergistically. Finally, both LPS and IL-1 alpha up-regulated ICAM-1 and VCAM-1 gene expression. These findings implicate duodenal fibroblasts in the initiation and/or regulation of intestinal inflammation.