趋化因子及趋化因子受体3在自身免疫疾病中的作用

人体在防御和清除入侵病原体等异物时,有一种使白细胞趋集的功能,有一些低分子量的物质能引起这种功能称之为趋化剂或趋化因子。这些小蛋白因其有定向细胞趋化作用而得名。经研究表明,趋化因子受体3（CXCR3）趋化因子可能在自身免疫内分泌疾病中起到致病作用。此外,血清中CXCR3趋化因子的判定可能辅助检测免疫活性。CXCR3和优先参与趋化Th1细胞的因子。该受体连接的趋化因子10（CXCL10）不仅参与白细胞募集,还诱导T细胞增殖的异源体和抗原的刺激。趋化因子10正调节Th1细胞产物并且负调节Th2细胞的产物。免疫反应纤维结合素（INF）产物可增强特异的炎症反应。当被激活或者发现炎症和肿瘤细胞后趋化因子受体3-B在内皮细胞中表达并且其结合的趋化因子10,趋化因子9和趋化因子11激活后产生血管抑制作用。     

CC类趋化因子亚家族与心肌梗死的研究进展

CC类趋化因子亚家族是趋化因子家族中成员最多、研究最广泛的一大类细胞因子,其主要功能参与炎症细胞激活、迁移、粘附等病理生理过程。大量研究表明,CC类趋化因子亚家族成员参与了心肌梗死后病理过程的各个阶段。其中研究最为深入的为单核细胞趋化蛋白-1（monocyte chemoattractant protein-1,MCP-1）及其受体CC趋化因子受体2（CC chemokine receptor 2,CCR2）,在心肌梗死后炎症期、增殖期及疤痕愈合期都发挥了重要作用从而影响梗死后心室重构。近年来,CC类趋化因子亚家族其他成员亦被逐渐揭示参与了心肌梗死的发展。本文结合以往大量文献将对CC类趋化因子亚家族在心肌梗死各个阶段中尤其是梗死后各期对于心室重构的影响进行综述,以期为今后的实验研究提供方向及疾病的预防和治疗提供药物靶点。     

趋化因子及其受体在神经系统发育中的作用

趋化因子是具有趋化作用的一类细胞因子,参与白细胞迁移的调控,在炎症中诱导性表达,与炎症过程密切相关,最初的研究主要局限于免疫系统。近几年来研究发现,趋化因子不仅参与神经系统疾病的炎症过程,而且在神经细胞成熟、发育等生理情况下组成性表达,发挥重要的生理调节作用,这一有趣的现象日益成为关注的焦点。本文主要针对趋化因子及其受体在神经系统发育中的作用及相关机制的研究成果予以综述,将有助于深入理解趋化因子与神经系统发育的关系,为进一步的研究提供依据。     

趋化因子CXCL16与临床疾病

趋化因子在T细胞迁移过程中起重要作用,CXCL16是作为磷脂酰丝氨酸和ox-LDL的清道夫受体的多功能趋化因子。血管内皮细胞同时表达功能性地分泌型和膜结合型CXCL16分子,分泌型CXCL16参与激活T淋巴细胞趋化。膜结合型CXCL16作为粘附分子,通过它的趋化因子活性区参与活化T淋巴细胞与血管内皮细胞之间的识别和直接粘附;促进大量的特异性炎症细胞浸润。研究证明趋化因子CXCL16在多种临床疾病中扮演起重要作用。本文综述了CXCL16与临床疾病的关系及其研究进展。     

炎症及炎症耐受模型筛选广谱趋化因子抑制肽

通过减少炎性组织或细胞趋化因子及炎性因子的表达量能将炎症性病理过程抑制在起始阶段．我们通过体外构建人外周血单个核细胞LPS激活的急性炎症模型及内毒素耐受模型,进行噬菌体肽库亲和筛选,ELISA检测与炎性PBMC的结合能力,分泌抑制实验筛选抑制性噬菌体克隆,经趋化抑制、竞争结合及生成抑制实验检测体外活性,大鼠足肿胀及关节炎模型检验多肽体内作用,SqRT-PCR检测趋化因子及TTP的mRNA水平,探讨其作用机制．筛选到的目标多肽CI-S5趋化抑制率达到48.72%,明显抑制噬菌体阳性克隆P15与LPS激活PBMC的结合,动物试验能明显降低大鼠足肿胀及关节炎症．机制研究显示,CI-S5多肽能降低3种趋化因子的表达量,并调节TTP使其表达增加,提示CI-S5能够靶向炎症前期PBMC,为炎症治疗提供了针对早期急性炎症反应的广谱小分子抑制肽．     

趋化因子ENA-78与肾脏疾病

体外实验中,各种肾脏细胞都能在特定刺激下表达趋化因子及受体。动物模型和人类肾脏疾病的肾组织中,炎症细胞浸润同时出现趋化因子及受体表达增多。ENA-78是一种来源广泛、生物功能多样的趋化因子,通过与其受体相互作用,引起中性粒细胞等白细胞的趋化、活化,参与肾脏疾病的发生、发展。     

CC趋化因子与心肌梗死的研究进展

CC类趋化因子亚家族是趋化因子家族中成员最多、研究最广泛的一大类细胞因子,其主要功能是参与炎症细胞激活、迁移、黏附等病理生理过程.大量研究表明,CC类趋化因子亚家族成员参与了心肌梗死后病理过程的各个阶段.其中研究最为深入的是单核细胞趋化蛋白1 (monocyte chemoattractant protein-1,MCP-1)及其受体CC趋化因子受体2 (CC chemokine receptor 2,CCR2). MCP-1和CCR2在心肌梗死后炎症期、增殖期及疤痕愈合期都发挥了重要作用从而影响梗死后心室重构.近年来,CC类趋化因子亚家族其他成员亦被逐渐揭示参与了心肌梗死的发展.本文结合以往大量文献,就CC类趋化因子亚家族在心肌梗死各个阶段中的作用,尤其是梗死后各期对于心室重构的影响进行综述,以期为今后的CC趋化因子研究提供方向,为相关疾病的预防和治疗研究提示潜在的药物靶点.     

趋化因子受体在炎症诱导痛觉中的作用

趋化因子受体最早是在研究白细胞迁移过程中发现的,它在大鼠和小鼠的背根神经节外周感觉神经细胞上也有表达.在炎症情况下,激活的趋化因子受体可以诱导神经细胞上一类重要的镇痛受体—μ-鸦片受体的异源性脱敏,抑制其功能;同时,激活的趋化因子受体还可以增强一类对于痛觉感受非常关键的受体——辣椒素受体的敏感性,使其敏化.趋化因子受体诱导的这2种效应可以通过Gi蛋白信号传导通路增强生物体对痛觉的敏感度.这些结果提示,趋化因子受体可能是免疫系统和神经系统之间交叉调节的桥梁.     

趋化因子CXCL12 及其受体CXCR4 在胶质瘤中的研究进展

CXCL12是趋化因子家族成员之一,是能够特异性结合其受体CXCR4发挥趋化性作用的细胞因子。最初,CXCL12及CXCR4被发现于炎症细胞,参与机体炎症、免疫等病理反应。接下来的几年中发现,它在机体发育、成熟过程中也有重要作用。如今,大量研究表明它与肿瘤的生长、侵袭及转移密切相关。据报道,在乳腺癌、肺癌、卵巢癌等二十余种肿瘤组织中发现CXCL12及CXCR4的表达,其中也包括中枢系统肿瘤-胶质瘤。CXCL12/CXCR4参与胶质瘤生长过程的多个步骤,包括肿瘤增殖、侵袭、转移等。有实验指出,转移灶的CXCR4表达水平较原发灶高,CXCR4有可能成为抑制胶质瘤生长、转移的重要靶目标。     

趋化因子CXCL12及其受体CXCR4在胶质瘤中的研究进展

CXCL12是趋化因子家族成员之一,是能够特异性结合其受体CXCR4发挥趋化性作用的细胞因子。最初,CXCL12及CXCR4被发现于炎症细胞,参与机体炎症、免疫等病理反应。接下来的几年中发现,它在机体发育、成熟过程中也有重要作用。如今,大量研究表明它与肿瘤的生长、侵袭及转移密切相关。据报道,在乳腺癌、肺癌、卵巢癌等二十余种肿瘤组织中发现CXCL12及CXCR4的表达,其中也包括中枢系统肿瘤-胶质瘤。CXCL12/CXCR4参与胶质瘤生长过程的多个步骤,包括肿瘤增殖、侵袭、转移等。有实验指出,转移灶的CXCR4表达水平较原发灶高,CXCR4有可能成为抑制胶质瘤生长、转移的重要靶目标。     

Endoplasmic Reticulum Stress Is Chronically Activated in Chronic Pancreatitis

The pathogenesis of chronic pancreatitis (CP) is poorly understood. Endoplasmic reticulum (ER) stress has now been recognized as a pathogenic event in many chronic diseases. However, ER stress has not been studied in CP, although pancreatic acinar cells seem to be especially vulnerable to ER dysfunction because of their dependence on high ER volume and functionality. Here, we aim to investigate ER stress in CP, study its pathogenesis in relation to trypsinogen activation (widely regarded as the key event of pancreatitis), and explore its mechanism, time course, and downstream consequences during pancreatic injury. CP was induced in mice by repeated episodes of acute pancreatitis (AP) based on caerulein hyperstimulation. ER stress leads to activation of unfolded protein response components that were measured in CP and AP. We show sustained up-regulation of unfolded protein response components ATF4, CHOP, GRP78, and XBP1 in CP. Overexpression of GRP78 and ATF4 in human CP confirmed the experimental findings. We used novel trypsinogen-7 knock-out mice (T^−/−), which lack intra-acinar trypsinogen activation, to clarify the relationship of ER stress to intra-acinar trypsinogen activation in pancreatic injury. Comparable activation of ER stress was seen in wild type and T^−/− mice. Induction of ER stress occurred through pathologic calcium signaling very early in the course of pancreatic injury. Our results establish that ER stress is chronically activated in CP and is induced early in pancreatic injury through pathologic calcium signaling independent of trypsinogen activation. ER stress may be an important pathogenic mechanism in pancreatitis that needs to be explored in future studies.     

Chemokines in acute respiratory distress syndrome

A characteristic feature of all inflammatory disorders is the excessive recruitment of leukocytes to the site of inflammation. The loss of control in trafficking these cells contributes to inflammatory diseases. Leukocyte recruitment is a well-orchestrated process that includes several protein families including the large cytokine subfamily of chemotactic cytokines, the chemokines. Chemokines and their receptors are involved in the pathogenesis of several diseases. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is caused by an uncontrolled systemic inflammatory response resulting from clinical events including major surgery, trauma, multiple transfusions, severe burns, pancreatitis, and sepsis. Systemic inflammatory response syndrome involves activation of alveolar macrophages and sequestered neutrophils in the lung. The clinical hallmarks of ARDS are severe hypoxemia, diffuse bilateral pulmonary infiltrates, and normal intracardiac filling pressures. The magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ARDS. Recent evidence shows that activated leukocytes and chemokines play a key role in the pathogenesis of ARDS. The expanding number of antagonists of chemokine receptors for inflammatory disorders may hold promise for new medicines to combat ARDS.     

Blockade of neurokinin-1 receptor attenuates CC and CXC chemokine production in experimental acute pancreatitis and associated lung injury

Accumulating evidence suggests the neuropeptide substance P (SP) and its receptor neurokinin-1 receptor (NK-1R) play a pivotal role in the pathogenesis of acute pancreatitis (AP). However, the mechanisms remain unclear. The present study investigated whether chemokines as proinflammatory molecules are involved in SP-NK-1R-related pathogenesis of this condition. We observed temporally and spatially selective chemokine responses in secretagogue caerulein-induced AP in mice. CC chemokines monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein-1alpha (MIP-1alpha) and CXC chemokine MIP-2 were elevated after AP induction. Time-dependent, tissue-specific analysis of their mRNA and protein expression suggested that they are early mediators in the condition and mediate local as well as systemic inflammatory responses. In contrast, another CC chemokine regulated on activation, T cells expressed and secreted (RANTES) was only involved in local pancreatic inflammation at a later stage of the disease. Either prophylactic or therapeutic treatment with a potent selective NK-1R antagonist CP-96,345 significantly suppressed caerulein-induced increase in MCP-1, MIP-1alpha, and MIP-2 expression but had no apparent effect on RANTES expression. The suppression effect of CP-96,345 on MCP-1, MIP-1alpha, and MIP-2 expression was concordantly demonstrated by immunohistochemistry, which, additionally, suggested that chemokine immunoreactivity was localized to acinar cells and the infiltrating leukocytes in the pancreas and alveolar macrophages, epithelial cells, and endothelial cells in the lungs. Our data suggest that SP, probably by acting via NK-1R on various chemokine-secreting cells in the pancreas and lungs, stimulates the release of chemokines that aggravate local AP and the development of its systemic sequelae.     

Cell Death and DAMPs in Acute Pancreatitis

Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP. Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP. DAMPs might be an attractive therapeutic target in AP.     

miR146a up-regulation is involved in small HA oligosaccharides-induced pro-inflammatory response in human chondrocytes

BackgroundSmall HA fragments are produced during cartilage degradation and their role seems to be preponderant during pathologies in which cartilage injury contribute to trigger and perpetuate the inflammatory mechanism.Several reports have increasingly shown that MicroRNAs (miRs), a small non-coding mRNAs are involved in the regulation of multiple biological processes, including cell proliferation and inflammation response in different pathologies, among them miR146a seems to be involved in inflammatory processes.MethodsStarting by these evidences we investigated the levels of miR146a and its correlation with inflammatory mediators in an experimental model of 6-mer HA-induced inflammatory response in human cultured chondrocytes.ResultsTreatment of chondrocytes with 6-mer HA showed up-regulation in inflammation parameters such as TLR-4, and CD44 receptors activation, IL-6, IL-1β and MMP-13 mRNA expression and proteins production, as well as NF-kB activation. We also revealed an up-regulation of miR146a. Transfection with a miR146a mimic or miR146a inhibitor produced the following effects: chondrocytes receiving miR146a mimic and then 6-mer HA significantly reduced inflammatory cytokines and MMP-13, while exposition of chondrocytes with miR146a inhibitor and then the 6-mer HA incremented the activity of damaging cytokines and MMP13. Expression of CD44 receptor was not affected by miR-146a treatments, while TLR-4 expression and NF-kB activation were modified.ConclusionsWe concluded that up-regulation of miR146a occurred in 6-mer HA-induced inflammation response may reduce the inflammatory cascade by modulating TLR-4 and NF-kB activation.General significanceThese results could be useful in develop new therapeutic strategies with the aim to reduce OA and RA incidence.     

Chemokine receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong?

Inflammation plays a pivotal role in exacerbating a wide array of human diseases. The chemokines are a group of proteins that control the movement and activation of the immune cells involved in all aspects of the inflammatory response. Recently, their cognate receptors have attracted considerable interest as therapeutic targets, in part because they are G-protein-coupled receptors, which have been antagonized successfully before by the pharmaceutical industry. Indeed, several companies have now reported the development of selective small-molecule chemokine receptor antagonists, and some of these compounds have even entered human Phase I clinical trials. Preclinical studies of the responsiveness of murine models of inflammation to either pharmacologic or genetic intervention have suggested that antagonism of some chemokine receptors may well prove to be a safe and efficacious approach to anti-inflammatory therapy.     

The dual role of neutrophil elastase in lung destruction and repair

The purpose of this review was to modify the prevailing view that neutrophil elastase (NE) is mainly a matrix-degrading enzyme. Recent observations indicate that the role of NE in inflammation is more complex than the simple degradation of extra-cellular matrix components. Several lines of evidence suggest that NE aims specifically at a variety of regulatory functions in local inflammatory processes. This enzyme can modulate many biological functions by promoting chemokine and cytokine activation and degradation, cytokine receptor shedding, proteolysis of cytokine binding proteins and the activation of different specific cell surface receptors. However, the current knowledge of regulatory mechanisms by which NE potentially regulates inflammatory processes is primarily derived from in vitro studies. The extent of these NE-dependent pathways and their relevance under various pathophysiological conditions remains poorly understood and a matter for further investigation. Recent studies suggest that NE not only plays a key role in lung destruction (emphysema) but can also modulate proliferative changes (fibrosis) in inflammatory processes. Thus, NE could be considered to have potential multiple roles in the pathogenesis of both emphysema and lung fibrosis.     

Protease Signaling to G Protein-Coupled Receptors: Implications for Inflammation and Pain

Proteases, like thrombin, trypsin, cathepsins, or tryptase, can signal to cells by cleaving in a specific manner, a family of G protein-coupled receptors, the protease-activated receptors (PARs). Proteases cleave the extracellular N-terminal domain of PARs to reveal tethered ligand domains that bind to and activate the receptors. Recent evidence has supported the involvement of PARs in inflammation and pain. Activation of PAR₁, PAR₂, and PAR₄ either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Recent studies suggest a crucial role for the different PARs in innate immune response. The role of PARs in the activation of pain pathways appears to be dual. Subinflammatory doses of PAR₂ agonists induce hyperalgesia and allodynia, and PAR₂ activation has been implicated in the generation of inflammatory hyperalgesia. In contrast, subinflammatory doses of PAR₁ or PAR₄ increase nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as analgesic mediators. PARs have to be considered as an additional subclass of G protein-coupled receptors that are active participants to inflammation and pain responses and that could constitute potential novel therapeutic targets.     

Myeloid‐specific GPCR kinase‐2 negatively regulates NF‐κB1p105‐ERK pathway and limits endotoxemic shock in mice

G‐protein‐coupled receptor kinase 2 (GRK2) is a member of a kinase family originally discovered for its role in the phosphorylation and desensitization of G‐protein‐coupled receptors. It is expressed in high levels in myeloid cells and its levels are altered in many inflammatory disorders including sepsis. To address the physiological role of myeloid cell‐specific GRK2 in inflammation, we generated mice bearing GRK2 deletion in myeloid cells (GRK2^?mye). GRK2^?mye mice exhibited exaggerated inflammatory cytokine/chemokine production, and organ injury in response to lipopolysaccharide (LPS, a TLR4 ligand) when compared to wild‐type littermates (GRK2^fl/fl). Consistent with this, peritoneal macrophages from GRK2^?mye mice showed enhanced inflammatory cytokine levels when stimulated with LPS. Our results further identify TLR4‐induced NF‐κB1p105‐ERK pathway to be selectively regulated by GRK2. LPS‐induced activation of NF‐κB1p105‐MEK‐ERK pathway is significantly enhanced in the GRK2^?mye macrophages compared to GRK2^fl/fl cells and importantly, inhibition of the p105 and ERK pathways in the GRK2^?mye macrophages, limits the enhanced production of LPS‐induced cytokines/chemokines. Taken together, our studies reveal previously undescribed negative regulatory role for GRK2 in TLR4‐induced p105‐ERK pathway as well as in the consequent inflammatory cytokine/chemokine production and endotoxemia in mice. J. Cell. Physiol. 226: 627–637, 2011. © 2010 Wiley‐Liss, Inc.