趋化因子及其受体在炎症性肠病中的作用

趋化因子是一类控制细胞定向迁移的细胞因子,其功能行使由趋化因子受体介导。在炎症性肠病中,许多趋化因子及其受体表达增加,并在发病机制上起着重要作用。针对趋化因子及其受体的靶向治疗能减轻炎症损伤,可望成为一种新的炎症性肠病的治疗方法。     

The role of chemokines in rheumatoid arthritis and osteoarthritis

The directed movement of immune cells is highly dependent on the chemokine network. Chemokines are key molecules early in the embryogenesis of lymph nodes and throughout adult life, where they regulate immune responses against pathogens. Although immune cells are best known for expressing chemokine receptors, through which they can respond to matching chemokines, endothelial cells also express chemokine receptors. The directed movement of endothelial cells facilitates angiogenesis. In chronic inflammatory conditions, such as rheumatoid arthritis (RA), chemokines are abundantly present at the site of inflammation and form a group of potential therapeutic targets. Some agents that block chemokine-chemokine receptor interaction are already under clinical investigation. The expression of chemokine receptors has also been found in cell types other than immune cells and endothelial cells. Chondrocytes, for instance, express several chemokine receptors. Elucidating their function may provide new insights into joint degradation in RA as well as in other conditions, including osteoarthritis (OA).     

The role of chemokines and chemokine receptors in mucosal inflammation

Chemokines represent a large family of small cytokines, the main function of which is the attraction of leukocytes to different tissues. Several chemokines and their receptors have been shown to play a critical role in lymphoid development, mucosal immunity, and inflammation. In this article we review recent advances in chemokine physiology and their potential role in the pathogenesis of mucosal inflammation. We also discuss the potential for the use of chemokine or chemokine receptor antagonists as novel therapies for inflammatory bowel disease.     

Role of C-C chemokines in Takayasu's arteritis disease

BACKGROUND: Takayasu's arteritis (TA) is a chronic obliterative inflammatory disease. Inflammatory cell infiltration and destruction of the vessel wall in TA strongly suggest that cell mediated immunological mechanisms play an important role in the pathogenesis of this disease. Therefore, in the present study our aim was to focus on the role of chemokines and adhesion molecules in patients with Takayasu's disease. METHODS: Twenty-one patients with clinically defined TA and 21 healthy control volunteers were recruited by using the standard criteria. Patients with TA were divided into those with clear-cut clinically active or inactive disease based on vasculitis activity score. RESULTS: MCP-1 and hRANTES were significantly increased in patients with TA as compared to controls. MCP-1 and hRANTES values were reliably able to distinguish between patients with active disease vs. subjects in remission. sVCAM-1 levels remained unaltered between patients and controls. CONCLUSIONS: C-C chemokines can be used as reliable markers/diagnostic tools in determining the activity of Takayasu's arteritis.     

The role of chemokines in atherosclerosis

Recruitment of mononuclear leukocytes and the migration, growth, and activation of the multiple cell types within atherosclerotic lesions are critical features of the chronic inflammatory and fibroproliferative response central to atherosclerosis. Attraction of leukocyte to tissues is controlled by chemokines, whose presence is well documented in atherosclerotic lesions. Studies using knockout and transgenic murine models have demonstrated that chemokine receptor/ligand interactions are of crucial importance in the development of atherosclerosis. Beyond their chemotactic effect on mononuclear leukocytes, chemokines may also interfere with smooth muscle cell migration and growth, as well as platelet activation and other well-defined features of the atherosclerotic process. There is no doubt that the identification of chemokines as important vascular signals has provided insights into our understanding of basic cellular and molecular mechanism of atherosclerosis. Thus, there is evidence that chemokine receptor/ligands could be identified as potential new targets for therapeutic intervention to prevent or control atherosclerosis in the near future.     

趋化因子及其受体在消化道肿瘤生物学行为中的作用

对趋化因子的最初认识是白细胞趋化性迁移作用,近年来,众多的研究表明,趋化因子及其受体对肿瘤细胞生长、血管生成、浸润和转移等过程有显著影响,这为探讨肿瘤的形成机制及抗肿瘤治疗提供了新的视角.此文就近年来有关趋化因子及其受体在消化道肿瘤生物学行为中作用的研究进展作一综述.     

Complementary DNA microarray analysis of chemokines and their receptors in allergic rhinitis.

OBJECTIVE: To analyze the roles of chemokines and their receptors in the pathogenesis of allergic rhinitis by observing the complementary DNA (cDNA) expression of the chemokines and their receptors in the nasal mucosa of patients with and without allergic rhinitis, using gene chips. METHODS: The total RNAs were isolated from the nasal mucosa of 20 allergic rhinitis patients and purified to messenger RNAs, and then reversely transcribed to cDNAs and incorporated with samples of fluorescence-labeled with Cy5-dUPT (rhinitis patient samples) or Cy3-dUTP (control samples of nonallergic nasal mucosa). Thirty-nine cDNAs of chemokines and their receptors were latticed into expression profile chips, which were hybridized with probes and then scanned with the computer to study gene expression according to the different fluorescence intensities. RESULTS: The cDNAs of the following chemokines were upregulated: CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL14, CCL17, CCL18, CCL19, CCL24, and CX3CL1 in most of the allergic rhinitis sample chips. CCR2, CCR3, CCR4, CCR5, CCR8 and CX3CR1 were the highly expressed receptor genes. Low expression of CXCL4 was found in these tissues. CONCLUSION: The T helper cell (T(H)) immune system is not well regulated in allergic rhinitis. Most of the upregulated genes we identified are of chemokines and their receptors that play important roles in T(H)2 response, and some are involved in the induction of allergic reaction, accumulation of inflammatory cells, and degranulation of sensitized cells. These findings can point to new strategies for allergic rhinitis immunotherapy.     

The role of calcium crystals and their effect on osteoarthritis pathogenesis

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive degeneration of articular cartilage. Due to its high prevalence and limited treatment options, OA has become one of the most disabling diseases in developed countries. In recent years, OA has been recognized as a heterogenic disease with various phenotypes. Calcium crystal-related endotypes, which are defined by either a distinct functional or pathobiological mechanism, are present in approximately 60% of all OA patients. Two different calcium crystals can accumulate in the joint and thereby calcify the cartilage matrix, which are basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) crystals. The formation of these crystals depends mainly on the balance of phosphate and pyrophosphate, which is regulated by specific proteins controlling the pyrophosphate metabolism. Dysregulation of these molecules subsequently leads to preferential formation of either BCP or CPP crystals. BCP crystals, on the one hand, are directly associated with OA severity and cartilage degradation. They are mostly located in the deeper cartilage layers and are associated with chondrocyte hypertrophy. CPP crystal deposition, on the other hand, is a hallmark of chondrocalcinosis and is associated with aging and chondrocyte senescence. Therefore, BCP and CPP crystals are associated with different chondrocyte phenotypes. However, BCP and CPP crystals are not mutually exclusive and can coexist in OA, creating a mixed endotype of OA. Both crystals clearly play a role in the pathogenesis of OA. However, the exact impact of each crystal type on either driving the disease progression or being a result of chondrocyte differentiation is still to be elucidated.     

The measurement of joint mechanics and their role in osteoarthritis genesis and progression

Justifying and improving mechanically based approaches to the treatment and prevention of osteoarthritis (OA) requires a critical understanding of the methods used to study joint mechanics and the current evidence for the role of mechanics in OA. The objectives of this article are (1) to summarize methods for assessing joint mechanics and their relative merits and limitations, (2) to describe the current evidence for the role of mechanics in OA initiation and progression, and (3) to describe some current treatment approaches that focus on modifying joint mechanics.     

The role of angiotensin II receptors and their antagonists in hypertension

The octapeptide angiotensin II is the major effector of the renin-angiotensin-aldosterone system. Angiotensin II causes a variety of potentially noxious biological effects, such as vasoconstriction, a rise in blood pressure, release of aldosterone, enhancement of the effect of catecholamines, and vascular and myocardial hypertrophy, including remodeling of the heart after myocardial infarction. All of these noxious effects of angiotensin II are mediated by angiotensin II receptors (AT receptors) of the AT1 subtype. The functional effects of AT2 receptors, which have been characterized by means of biochemical techniques, are so far not clearly identified. Stimulation of the AT2 receptor by means of angiotensin II is assumed to counteract vascular/myocardial remodeling and possibly to induce vasodilation. Accordingly, AT1 and AT2 receptors are believed to provoke opposite effects. It has drawn attention that fetal tissues contain a high density of AT2 receptors, which is lowered significantly after birth. The identification and analysis of AT receptors has been greatly stimulated by the development of non-peptidergic AT1 receptor antagonists, of which losartan is the prototype. It is so far unclear whether AT receptors are activated in hypertensive disease. A survey will be made of the hemodynamic effects of AT1 receptor antagonists, their interaction with AT receptors, and the probably important role of the sympathetic nervous system involved in the antihypertensive action of AT receptor antagonists.     

C-C chemokines, pivotal in protection against HIV type 1 infection

Exposure to HIV type 1 (HIV-1) does not usually lead to infection. Although this could be because of insufficient virus titer, there is now abundant evidence that some individuals resist infection even when directly exposed to a high titer of HIV. This protection recently has been correlated with homozygous mutations of an HIV-1 coreceptor, namely CCR5, the receptor for the β-chemokines. Moreover, earlier results already had shown that the same chemokines markedly suppress the nonsyncitial inducing variants of HIV-1, the chief virus type transmitted from person to person. CCR5 mutation, as a unique mechanism of protection, is, however, suspect because HIV-1 variants can use other chemokine receptors as their coreceptor. Moreover, recent results have established that infection can indeed sometimes occur with such mutations. Here, we report on transient natural resistance over time of most of 128 hemophiliacs who were inoculated repeatedly with HIV-1-contaminated Factor VIII concentrate from plasma during 1980–1985 before the development of the HIV blood test. Furthermore, and remarkably, 14 subjects remain uninfected to this date, and in these subjects we found homozygous CCR5 mutations in none but in most of them overproduction of β chemokines. In vitro experiments confirmed the potent anti-HIV suppressive effect of these chemokines.     

The role of chemokines in Henoch Schonlein Purpura

Background The pathogenesis of Henoch Schonlein Purpura is incompletely understood and the role of chemokines is unknown. Objective To investigate the levels of CC chemokines, eotaxin, TARC, and CXC chemokine IP-10 in Henoch Schonlein Purpura. Methods Three groups of children were enrolled in the study: Henoch Schonlein Purpura in active stage (n = 26), Henoch Schonlein Purpura in remission phase (n = 26) and healthy children (n = 18). Levels of eotaxin, TARC, and IP-10 were determined in plasma using ELISA. Results No significant difference was observed in the plasma level of eotaxin and TARC levels between the HSP and healthy children (>0.05). We could not find any significant difference between acute phase of the disease and convalescent phase in eotaxin and TARC levels (P > 0.05). We have suggested significant decreases in plasma IP-10 in the acute phase of the disease compared with the convalescent phase (P < 0.05). There was a significant difference in IP-10 levels between active stage and healthy controls, too (<0.05). We could not find any significant correlation between chemokine levels and system involvement (>0.05). Conclusion Our study shows that plasma level of eotaxin and TARC levels do not differ between the HSP and healthy children. But, decreasing the release of the Th1 chemokine IP-10 in HSP active stage may show that in HSP, there is no shift to Th1 lymphocytes in children with HSP. Further investigations are warranted to more fully explore and understand the production of and potential role of these chemokines in HSP.     

The role of chemokines in virus-associated asthma exacerbations

Asthma is a chronic disease characterized by mast cell activation, mucus hypersecretion, airway obstruction, influx and activation of eosinophils, and generation of a predominant T-helper type 2-based cytokine environment. In individuals with established asthma, acute exacerbations requiring hospitalization result primarily from pulmonary viral infection, such as with influenza, rhinovirus, or respiratory syncytial virus. The mechanism for viral exacerbation of the asthmatic response is unclear, but evidence points to a key role for chemokines, a class of cytokines that are important in leukocyte recruitment, inflammatory cell activation, and T-cell differentiation. In this review, we focus on the chemokines upregulated in acute viral-induced exacerbation and examine their role in promoting the virus-induced pathophysiologic response in asthmatic individuals.     

Toll-like receptors and their role in gastrointestinal disease

The innate immune response to invading pathogens is centred upon a family of non-clonal, germline-encoded pattern recognition receptors (PRRs), the Toll-like receptors (TLRs). These provide specificity for a vast range of microbial pathogens, and offer an immediate anti-microbial response system. Thirteen mammalian TLRs have been described; 10 are expressed in humans, each responsible for the recognition of distinct, invariant microbial structures originating from bacteria, viruses, fungi and protozoa. The two most thoroughly studied are TLR4 and TLR2, the PRRs for Gram-negative and Gram-positive bacterial products, respectively. TLR4 is also the major receptor recognising endogenous ligands released from damaged or dying cells. Activation of a TLR by its relevant ligand rapidly ignites a complex intracellular signaling cascade that ultimately results in upregulation of inflammatory genes and production of proinflammatory cytokines, interferons and recruitment of myeloid cells. It also stimulates expression, upon antigen presenting cells, of co-stimulatory molecules required to induce an adaptive immune response. Whilst a robust TLR response is critical for survival and defence against invading pathogens, inappropriate signaling in response to alterations in the local microflora environment can be detrimental. Such 'unhelpful TLR responses' could form the basis for a large number of gastrointestinal and liver disorders, including inflammatory bowel disease, viral hepatitis, autoimmune liver diseases and hepatic fibrosis. As our understanding of TLRs expands, the pathogenesis of a number of gastrointestinal disorders will be further elucidated, and this offers potential for specific therapies aimed directly at TLR signaling.     

Chemokine receptors and their role in vascular biology

Chemokines play an important role in the process of leukocyte recruitment and activation at sites of inflammation. Until recently, the actions of chemokines and the expression of their receptors have only been described on different leukocyte populations. However, increasing evidence has suggested that non-haematopoietic cell types are capable of binding and responding to a number of chemokines. The functional expression of certain chemokine receptors has recently been described on vascular endothelial and smooth muscle cells. These findings provide new insight into the activities of chemokines and indicate that these molecules have a more widespread cellular target than first envisaged. Studies carried out to date indicate that chemokines and their respective receptors play an important role in the regulation of angiogenesis and angiostasis. They may also be involved in developmental and pathological processes such as organ vascularization, embryogenesis and arteriosclerosis.     

The role of imaging in osteoarthritis

Osteoarthritis (OA) is the most prevalent joint disorder with no approved disease-modifying treatment available. The importance of imaging in assessing all joint structures involved in the disease process, including articular cartilage, meniscus, subarticular bone marrow, and synovium for diagnosis, prognostication, and follow-up, has been well recognized. In daily clinical practice, conventional radiography is still the most commonly used imaging technique for the evaluation of a patient with known or suspected OA and radiographic outcome measures are still the only approved end point by regulatory authorities in clinical trials.The ability of magnetic resonance imaging (MRI) to visualize all joint structures in three-dimensional fashion including tissue ultrastructure has markedly deepened our understanding of the natural history of the disease. This article describes the roles and limitations of different imaging modalities for clinical practice and research in OA, with a focus on radiography and MRI and an emphasis on the knee joint.     

The role of chemokines in the pathogenesis of scleroderma

PURPOSE OF REVIEW: The triad of pathologic changes that defines systemic sclerosis (scleroderma) includes immune system activation with autoimmunity; an obliterative, proliferative small vessel vasculopathy; and fibrosis. Available data suggest that several cytokines, including chemokines, contribute to the development of scleroderma complications. This review focuses on chemokines and their contribution to tissue fibrosis and pulmonary hypertension in scleroderma. RECENT FINDINGS: Proteins and mRNAs for monocyte chemoattractant protein-1; pulmonary and activation-regulated chemokine; macrophage inflammatory protein-1, regulated upon activation normal T cell expressed and secreted; interleukin-8; and transforming growth factor-beta have been found in increased amounts in blood or involved tissue from scleroderma patients. These factors are likely to contribute directly to tissue damage in scleroderma through several pathways, including stimulation of extracellular matrix production, induction of TGF-beta production and activation, and chemoattraction of T cells and nonspecific inflammatory cells into tissues. SUMMARY: Multiple chemokines are part of the pathologic network that causes tissue damage in scleroderma, and, as such, may provide therapeutic targets in scleroderma.