IL—23研究进展

IL-23是新近发现的一种促炎性细胞因子，隶属于IL-12分子家族。类似于IL-12，IL-23是由两种亚单位(p40和p19)通过二硫键形成的异二聚体分子，二者的生物学功能也有很多相似之处，但并不完全相同，提示IL-23在维护机体内环境的稳定以及病理条件下免疫系统的激活等方面发挥着独特的生物学作用。     

Inhibitory Effect of Water‐Soluble Chitosan on TNF‐α and IL‐8 Secretion from HMC‐1 Cells

Mast cells are known to play an active role as effector cells in allergic inflammation and in diverse immunological and pathological processes. Activated mast cell‐derived pro‐inflammatory cytokines are important pathologic factors of progression of allergic inflammation. In this study, we investigated whether pro‐inflammatory cytokines (TNF‐α and IL‐8) can be induced by calcium stimulation in HMC‐1 cells, and high molecular weight water‐soluble chitosan (WSC) can inhibit the production of these cytokines. We provided evidence that the secretion of TNF‐α and IL‐8 from HMC‐1 cells was induced by Ca^{2 +}‐ionophore A23187 or Ca^{2 +}‐ATPase inhibitor TSG. Treatment of WSC (10 µg/ml) prior to stimulation with calcium agonists significantly blocked the secretion of TNF‐α by 65.1% for A23187 and 87.7% for TSG. IL‐8 secretion in response to A23187 or TSG was inhibited by 49.2% for A23187 and 34.1% for TSG, respectively, compared to absence of WSC. These results suggest that WSC has potential regulatory effects on allergic inflammatory diseases by down‐modulating Ca^{2 +}‐induced mast cell activation.     

IL‐1β Induces and TGF‐β Reduces Vitamin D3‐Induced Bone Resorption in Mouse Calvarial Bone Cells

Bone cells produce multiple growth factors and cytokines that have effects on bone metabolism and can be incorporated into the bone matrix. The present study was designed to extend these observations by examining the interactions between transforming growth factor‐β (TGF‐β) or interleukin‐1β (IL‐1β) and bone cells in a rat long bone culture model. IL‐1β regulates several activities of the osteoblast cells derived from rat long bone explants in vitro. IL‐1β stimulated cellular proliferation and the synthesis of prostaglandin E₂ and plasminogen activator activity in the cultured cells in a dose‐dependent manner. TGF‐β is present in the bone matrix and potentially can be released during bone resorption. TGF‐β reduced basal bone resorption and inhibited vitamin D₃ [1,25(OH)₂D₃]‐induced bone resorption in rat long bone cells. These studies support the role of IL‐1β in the pathological modulation of bone cell metabolism, with regard to implication in the pathogenesis of osteoporosis by IL‐1β, and that TGF‐β is positively inhibiting the bone resorption.     

IL23R: a susceptibility locus for celiac disease and multiple sclerosis?

Recent studies have shown association of the IL23R gene with inflammatory bowel disease, psoriasis and ankylosing spondylitis. We aimed at studying the involvement of IL23R in celiac disease (CD) and multiple sclerosis (MS). We performed a case-control study including 598 patients with CD, 414 with MS and 546 healthy controls, all of them white Spaniards. All samples were genotyped for two single nucleotide polymorphisms: rs7517847 and rs11209026 (Arg381Gln). Statistical analyses were performed using chi(2-)tests or the Fisher's exact test. The minor allele (Gln) of the coding variant Arg381Gln was significantly increased in CD and MS patients when compared to controls (8% in CD vs 6% in controls, P=0.02; 9% in MS, P=0.006). In MS, a stronger effect was observed in patients showing primary-progressive disease (16%, P=0.004). Moreover, heterozygotes for rs7517847 were significantly increased in this group of MS patients (81% in MS vs 48% in controls, P=0.0002). In conclusion, contrary to what has been described previously, the less frequent allele of the functional polymorphism Arg381Gln (rs11209026) seems to be increasing susceptibility to CD and MS, although in this last group of patients a stronger effect is observed in patients affected of a primary-progressive form.     

The Interleukin (IL)‐2 Family Cytokines: Survival and Proliferation Signaling Pathways in T Lymphocytes

Lymphocyte populations in the immune system are maintained by a well-organized balance between cellular proliferation, cellular survival and programmed cell death (apoptosis(. One of the primary functions of many cytokines is to coordinate these processes. In particular, the interleukin (IL(‐2 family of cytokines, which consists of six cytokines ‐IL‐2, IL‐4, IL‐7, IL‐9, IL‐15 and IL‐21) that all share a common receptor subunit (gc), plays a major role in promoting and maintaining T lymphocyte populations. The details of the molecular signaling pathways mediated by these cytokines have not been fully elucidated. However, the three major pathways clearly involved include the JAK/STAT, MAPK and phosphatidylinositol 3‐kinase ‐PI3K‐ pathways. The details of these pathways as they apply to the IL‐2 family of cytokines is discussed, with a focus on their roles in proliferation and survival signaling.     

IL-23及IL23/Th17通路与HBV宫内感染的相关研究

乙型病毒性肝炎是由乙型肝炎病毒（HBV）造成的可能威胁生命的肝脏感染。我国是乙肝的高流行区,乙型肝炎病毒最常见的传播途径是母婴传播或在幼儿期的儿童间传播。以往研究表明,孕妇体内Th1/Th2细胞免疫失衡是导致HBV宫内感染的重要因素,而对于新近发现的与白细胞介素-23（IL-23）相关,能分泌白细胞介素-17（IL-17）的CD4＋T细胞亚群即Th17细胞,或许能为我们提供新的思路。下面就乙型病毒性肝炎的发病机制及研究现状、IL-23与乙肝合并妊娠及宫内感染等疾病的关系及此免疫通路活化在乙肝合并妊娠及宫内感染的致病过程中所起的作用作一综述。     

Selective Isolation and Identification of HLA‐DR‐Associated Naturally Processed and Presented Epitope Peptides

Activation of CD4 helper T‐cells is mediated by the presentation of antigenic peptides in context of self‐MHC class II molecules. So far, the rules after which antigen‐presenting cells (APC) select a particular epitope within a given protein antigen have been not fully elucidated. Nevertheless, immunoaffinity purification of APC‐derived MHC class II molecules and the subsequent elutions of their with associated naturally processed and presented peptide epitopes (NPPE) have helped tremendously in understanding the nature of this rather complex process. In the present study, a novel approach for identifying such NPPEs is introduced, which is based on the culture of APCs in a completely protein‐free medium during the antigen presenting process. These APCs do still express a high level of MHC class II as determined by HLA‐DR cell surface staining, but the repertoire of the associated NPPEs is drastically reduced when compared to peptides eluted from cells maintained under normal culture condition. Actually, reverse phase‐high pressure liquid chromatography (RP‐HPLC) revealed that the entire NPPE repertoire consisted of less than ten major peaks, which is more than a 100‐fold reduction of background peptide peaks as seen in cells from serum‐containing culture conditions. Feeding APCs with exogenous antigens further confirmed the advantage of this novel system. While exogenous antigen‐derived peptide peaks in an NPPE‐eluate from RP‐HPLC are hardly to detect by conventional procedures, the very low background of serum‐ and protein‐free cultured APCs immensely facilitated this process, providing an improved tool for the identification and characterization of NPPEs.     

Carvedilol Modulates In‐Vitro Granulocyte‐Macrophage Colony‐Stimulating Factor‐Induced Interleukin‐10 Production in U937 Cells and Human Monocytes

Both granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and interleukin‐10 (IL‐10) are important mediators regulating inflammatory responses. Inflammatory processes have an important role in atherogenesis. In this paper, the effects of carvedilol on GM‐CSF‐induced IL‐10 production were examined on human monocytic cell line, U937, and purified human monocytes. First, we showed that one‐time carvedilol pretreatment at concentrations 0.3–10 μM dose‐dependently inhibited GM‐CSF‐induced IL‐10 production in U937 cells. In addition, we found carvedilol to be non‐cytotoxic at concentrations equal to or less than 10 μM. However, at concentrations higher than 10 μM, carvedilol induced programmed cell death in U937 cells. The inhibition of GM‐CSF‐induced IL‐10 production by carvedilol was also observed at the expression of mRNA. Furthermore, the inhibition of IL‐10 production was demonstrated in GM‐CSF‐activated purified human peripheral blood monocytes. Finally, long‐term carvedilol pretreatment of U937 cells up to 2 months at concentrations of 1.0 μM mildly enhanced the IL‐10 production. Our observations that carvedilol modulated GM‐CSF‐induced IL‐10 production may have some implication in understanding the broad‐spectrum effects of carvedilol in regulating inflammatory reactions.     

Hyper‐responsive Toll‐like receptor 7 and 9 activation in NADPH oxidase‐deficient B lymphoblasts

Chronic granulomatous disease (CGD) is an inherited immunodeficiency linked with mutations in the multi-subunit leucocyte NADPH oxidase. Myeloid-derived phagocytic cells deficient in NADPH oxidase fail to produce sufficient levels of reactive oxygen species to clear engulfed pathogens. In this study we show that oxidase also influences B-cell functions, including responses to single-stranded RNA or unmethylated DNA by endosomal Toll-like receptors (TLRs) 7 and 9. In response to TLR7/9 ligands, B-cell lines derived from patients with CGD with mutations in either the NADPH oxidase p40^phox or p47^phox subunits produced only low levels of reactive oxygen species. Remarkably, cytokine secretion and p38 mitogen-activated protein kinase activation by these oxidase-deficient B cells was significantly increased upon TLR7/9 activation when compared with oxidase-sufficient B cells. Increased TLR responsiveness was also detected in B cells from oxidase-deficient mice. NADPH oxidase-deficient patient-derived B cells also expressed enhanced levels of TLR7 and TLR9 mRNA and protein compared with the same cells reconstituted to restore oxidase activity. These data demonstrate that the loss of oxidase function associated with CGD can significantly impact B-cell TLR signalling in response to nucleic acids with potential repercussions for auto-reactivity in patients.     

血清中sCD23和IL－4水平与AICAH的关系

血清中ｓＣＤ２３和ＩＬ－４水平与ＡＩＣＡＨ的关系［英］／Ａｌ－Ｊａｎａｄａｌ…／／ＣｌｉｎｉＩｍｍｕｎｏｌａｎｄＩｍ－ｍｕｎｏｐａｔｈｏｌｏｇｙ．—１９９４，７１（１）．—３３～３７已知ｓＣＤ２３，ＩＬ－４和可溶性ＩＬ－２Ｒ（ｓＩＬ－２Ｒ）在一定的自...     

Open‐ and closed‐loop smooth‐pursuit eye movements in normal children: An analysis of a step‐ramp task

We previously reported that the visual ability to track a moving target (smooth‐pursuit tracking) improves as children age from 8 to 15 years old. This study used infrared oculography during step‐ramp tasks to determine whether the age‐related improvement in smooth‐pursuit tracking is due to developmental changes in the ability to perceive and match eye velocity to target velocity (open‐loop tracking). Infrared oculography was used to assess the ability to track a moving stimulus (smooth‐pursuit tracking) during step‐ramp tasks in 51 normal children between 8 and 15 years old. The first 100 msec of tracking (initial pursuit) occurs before any visual feedback (open‐loop tracking) and represents sensorimotor transformation. Ongoing pursuit (measured by smooth‐pursuit gain) includes feedback information as to the success of pursuit (closed‐loop pursuit) and depends on sensorimotor transformation as well as higher order abilities, including the ability to sustain focused attention. Open‐loop pursuit is not affected by age of the subject. In contrast, during closed‐loop pursuit, when target step and target motion are in opposite directions, age is significantly correlated with closed‐loop pursuit gain, Spearman's R = 0.40, p < .003. The ability to perceive and match eye velocity to target velocity is fully developed by 8 years of age.     

Theory of mind and perceptual context‐processing in schizophrenia

Introduction. A series of studies have suggested that schizophrenia patients are deficient in theory of mind (ToM). However, the cognitive mechanisms underlying ToM deficits in schizophrenia are largely unknown. The present study examined the hypothesis that impaired ToM in schizophrenia can be understood as a deficit in context processing.

Methods. Disorganised schizophrenia patients (N = 12), nondisorganised schizophrenia patients (N = 36), and nonpsychotic psychiatric patients (N = 26) were tested on three ToM tasks and a visual size perception task, a measure of perceptual context processing. In addition, statistical analyses were carried out which compared chronic, treatment‐refractory schizophrenia patients (N = 28) to those with an episodic course of illness (N = 20).

Results. Overall, ToM performance was linked to deficits in context processing in schizophrenia patients. Statistical comparisons showed that disorganised as well as chronic schizophrenia patients were more impaired in ToM but more accurate in a visual size perception task where perceptual context is misleading.

Conclusions. This pattern of results is interpreted as indicating a possible link between deficits in ToM and perceptual context processing, which together with deficits in perceptual grouping, are part of a broader dysfunction in cognitive coordination in schizophrenia.     

Lexical‐semantic retention and speech production:further evidence from normal and brain‐damaged participants for a phrasal scope of planning

The present study investigated the scope of planning in speech production by examining onset latencies for sentences describing moving picture displays. The experimental sentences began with either a simple or complex noun phrase, but were matched in length and content words. Results from young and old normal participants replicated previous findings of Smith and Wheeldon (1999) in showing longer onset latencies for sentences beginning with a complex noun phrase, supporting a phrasal scope of planning. Two aphasic patients were tested who, in previous studies, had shown a short‐term memory deficit either in semantic retention (patient ML)or in phonological retention (patient EA). Patient ML showed a markedly greater disadvantage for the sentences beginning with a complex noun phrase whereas EAshowed an effect within normal range. The present results from the patients, together with those from previous studies, indicate that the phrasal planning is occurring at a lexical‐semantic level using a capacity that is also involved in comprehension.     

Association study between the IL4, IL13, IRF1 and UGRP1 genes in chromosomal 5q31 region and Chinese Graves’ disease

Graves disease (GD) was believed to be a polygenic disease. Several chromosomal regions were linked to GD, and the 5q31 chromosome regions containing several interleukin genes cluster were worth observing. In this study, IL4, IL13, IRF1 and UGRP1 genes were sequenced, and 5, 3, 7 and 7 polymorphisms respectively were discovered. Then an extended association study for the attracting polymorphisms was performed with 146 sporadic Graves patients, 142 unrelated controls and the 54 multiplex Graves families. However, the genotype and allele frequency distribution of these polymorphisms had similar distribution between the Graves patients and unrelated controls, and transmission disequilibrium tests indicated that none of them showed dominant transmission from heterozygous parents to the affected offsprings. Comparison of the clinical variables of the Graves patients indicated that the onset ages of the patients carrying TT at IRF1 6477 T/G locus were younger than those having variant allele (TG, GG); the difference was of statistical significance (P=0.005, Pc=0.020). Our association study revealed that, IL4, IL13, IRF1 and UGRP1 genes in chromosomal 5q31 regions might not confer susceptibility to Chinese GD. But those individuals who were TT homozygous at IRF1 6477 T/G locus seemed to be attacked by GD much earlier than others.Huang Wei and Teng Weiping equally contributed to this work