病毒趋化因子与病毒趋化因子受体

趋化因子和趋化因子受体的生物学是目前生物学的研究热点之一。病毒趋化因子及病毒趋化因子受体的发现使我们能从新的视角研究病毒的致病机理,从而探寻新的预防和治疗方法。本文综述了这一领域的最新发现和研究进展。     

趋化因子及其受体在炎症中作用的研究进展

趋化因子是能够激发白细胞趋化性的小分子分泌性蛋白质,是可受化学诱导物及细胞因子调节、并能刺激细胞趋化运动的一类细胞因子.趋化因子将循环中的淋巴细胞募集到组织损伤或炎症反应部位.早期对趋化因子的研究是基于其在炎症中的功能.最近发现趋化因子及其受体和机体内单核细胞的迁移,适应性免疫应答以及多种疾病的发病机理相关.趋化因子受体作为炎症和免疫应答的调控分子而成为多种药物的靶向分子.临床上已经开始利用趋化因子的拈抗剂治疗炎症疾病,本篇旨在阐述趋化因子及其受体在炎症疾病中的作用以及这些趋化因子在临床上的应用.     

Role of chemokines and chemokine receptors in the gastrointestinal tract

The pathological association between leucocytes and gastrointestinal diseases has long been recognized. Chemokines are a large family of chemotactic cytokines whose fundamental role is the recruitment of leucocytes to tissues. Although chemokines and their receptors are considered to be mediators of inflammation and tissue injury in several inflammatory diseases, their precise role in the pathophysiology of gastrointestinal diseases remains incompletely understood. Nonetheless, by virtue of their expression and localization at sites of gastrointestinal tissue injury and inflammation, a number of investigators have suggested a vital role for chemokines and their receptors in the pathophysiology of gastrointestinal diseases. This short review examines the role of chemokines and their receptors in the gastrointestinal tract with an emphasis on their involvement in the regulation of intestinal and hepatic inflammation.     

Regulation of experimental autoimmune encephalomyelitis by chemokines and chemokine receptors

Experimental autoimmune encephalomyelitis (EAE) isa, T cell mediated demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS). In sights into the pathogenesis of this model may help scientists understand the human disease and aid in rational drug discovery. In this review we summarize the role of chemokines and chemokine receptors in disease pathogenesis and suggest a pathway of events that leads to demyelination and subsequent clinical disease manifestation.     

DAMGO-induced expression of chemokines and chemokine receptors: the role of TGF-beta1

Studies from a number of laboratories suggest that modulation of cytokine expression plays an integral role in the immunomodulatory activity of opioids. Previously, our laboratory reported that activation of the mu-opioid receptor induced the expression of CCL2, CCL5, and CXCL10, as well as CCR5 and CXCR4. Previous work has also suggested the possibility that TGF-beta may participate in the opioid-induced regulation of immune competence, and in the present study, we set out to determine the role of this cytokine in the control of chemokine and chemokine receptor expression. We found that D-ala(2),N-Me-Phe(4)-Gly-ol(5)enkephalin (DAMGO), a highly selective mu-opioid agonist, induced the expression of TGF-beta1 expression at the protein and mRNA levels. In turn, the addition of TGF-beta1 was found to induce CCL5 and CXCR4 expression but not CCL2, CXCL10, or CCR5. Further analysis showed that pretreatment with neutralizing anti-TGF-beta1 blocked the ability of DAMGO to induce CCL5 or CXCR4. Similarly, pretreatment with cycloheximide prevented CCL5 or CXCR4 mRNA expression, consistent with the observation that DAMGO induction of chemokine and chemokine receptor expression requires newly synthesized TGF-beta1 protein. These results describe a common molecular basis for the activation of chemokine and chemokine receptor expression and may permit the development of strategies to inhibit certain undesirable immunological properties of micro-opioid agonists such as morphine and heroin.     

Genetic variants in the chemokines and chemokine receptors in Chagas disease

Clinical symptoms of Chagas' disease occur in 30% of the individuals infected with Trypanosoma cruzi and are characterised by heart inflammation and dysfunction. Chemokines and chemokine receptors control the migration of leukocytes during the inflammatory process and are involved in the modulation of Th1 or Th2 responses. To determine their influence, we investigated the possible role of CCL5/RANTES and CXCL8/IL8 chemokines, and CCR2 and CCR5 chemokines receptors cluster gene polymorphisms with the development of chagasic cardiomyopathy. Our study included 260 Chagas seropositive individuals (asymptomatic, n=130; cardiomyopathic, n=130) from an endemic area of Colombia. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP genotyping assay. We found statistically significant differences in the distribution of the CCR5 human haplogroup (HH)-A (p=0.027; OR=3.78, 95% CI=1.04-13.72). Moreover, we found that the CCR5-2733 G and CCR5-2554 T alleles are associated, respectively, with a reduced risk of susceptibility and severity to develop chagasic cardiomyopathy. No other associations were found to be significant for the other polymorphisms analysed in the CCR5, CCR2, CCL5/RANTES and CXCL8/IL8 genes. Our data suggest that the analysed chemokines and chemokine receptor genetic variants have a weak but important association with the development of chagasic cardiomyopathy in the population under study.     

The role of chemokines and chemokine receptors in alloantigen-independent and alloantigen-dependent transplantation injury

Transplantation injury and rejection involves the interplay of innate and acquired immune responses. Immune-related injury manifests itself in three temporal phases: early innate immune driven alloantigen-independent injury, acquired immune driven alloantigen-dependent injury, and chronic injury. Sequential waves of chemokine expression play a central role in regulating graft injury through the recruitment of phagocytes shortly after transplantation and activated lymphocytes and phagocytes in the weeks and years following transplantation. This review focuses on recent studies demonstrating the role of chemokines in transplantation.     

Re-evaluation of the chicken MIP family of chemokines and their receptors suggests that CCL5 is the prototypic MIP family chemokine, and that different species have developed different repertoires of both the CC chemokines and their receptors

Analysis of the chicken genome has shown that the chicken has a different repertoire of chemokines and chemokine receptors to those of mammals and other species. In this study, we report the sequencing and analysis of a bacterial artificial chromosome containing the entire chicken MIP family CC chemokine cluster. The gene duplication and divergence events that have taken place in mammals do not appear to have occurred as extensively in the avian lineage, as chickens possess fewer MIP family chemokine genes than humans or mice. We previously proposed that the four chicken MIP family members be named chicken (ch) CCLi1-4, according to their position on chicken chromosome 19, until such time as further analysis could determine if any of them were direct orthologues of mammalian MIP family members. Our analysis herein, combined with that of others, suggests that chCCLi4 is the orthologue of mammalian CCL5, and that chCCLi3 (K203) may be an orthologue of human CCL16. The other two chemokines do not have obvious orthologues, and thus we propose that they should still be called chCCLi1 and chCCLi2, until their biological function is further characterised. A similar pattern applies to the MIP family chemokine receptors, with only three receptor genes present at the relevant locus in the chicken genome, compared to four in man and mouse (CCR1, CCR2, CCR3 and CCR5). Of the three chicken receptor genes, only two look likely to be receptors for the MIP family chemokines, the third grouping with human, mouse and chicken CCR8 in phylogenetic analysis. The two chicken MIP CC receptors (CCRs) are not direct orthologues of the mammalian MIP CCRs.     

The role of HIV-related chemokine receptors and chemokines in human erythropoiesis in vitro

In order to better define the role of HIV-related chemokines in human erythropoiesis we studied: A) the expression of chemokine receptors, both on human CD34(+) cells which include erythroid progenitors and on more mature erythroid cells; B) the functionality of these receptors by calcium flux, chemotaxis assay and phosphorylation of mitogen-activated protein kinases (MAPK) p42/44 (ERK1/ERK2) and AKT, and finally C) the influence of chemokines on BFU-E formation. We found that HIV-related chemokine receptor CXCR4, but not CCR5, is detectable on human CD34(+) BFU-E cells. CXCR4 surface expression decreased during erythroid maturation, although CXCR4 mRNA was still present in cells isolated from differentiated erythroid colonies. SDF-1, a CXCR4 ligand, induced calcium flux and phosphorylation of MAPK (p42/44) and AKT in CD34(+)KIT(+) bone marrow mononuclear cells which contain BFU-E, as well as chemotactic activity of both human CD34(+) BFU-E progenitors and erythroid cells isolated from day 2-6 BFU-E colonies. Responsiveness to SDF-1 decreased when the cells differentiated to the point of surface expression of the erythroid-specific marker Glycophorin-A. In contrast, the CCR5 ligands (macrophage inflammatory protein-1alpha [MIP-1alpha], MIP-1beta, and RANTES) did not activate calcium flux, MAPK and AKT phosphorylation or chemotaxis of CD34(+)KIT(+) cells or cells isolated from the BFU-E colonies. Interestingly, none of the chemokines tested in this study had any effect on BFU-E colony formation. In conclusion, only CXCR4 is functional, and its specific ligand SDF-1 may therefore play an important role in the homing and/or retention of early erythroid precursors in the bone marrow environment.     

A family tree of vertebrate chemokine receptors for a unified nomenclature

Chemokines receptors are involved in the recruitment of various cell types in inflammatory and physiological conditions. There are 23 known chemokine receptor genes in the human genome. However, it is still unclear how many chemokine receptors exist in the genomes of various vertebrate species other than human and mouse. Moreover, the orthologous relationships are often obscure between the genes of higher and lower vertebrates. In order to provide a basis for a unified nomenclature system of the vertebrate chemokine receptor gene family, we have analysed the chemokine receptor genes from the genomes of 16 vertebrate species, and classify them into 29 orthologous groups using phylogenetic and comparative genomic analyses. The results reveal a continuous gene birth and death process during the vertebrate evolution and an interesting evolutionary history of the chemokine receptor genes after the emergence in agnathans.     

Expression of CC and CXC chemokines and chemokine receptors in human leprosy skin lesions

We have investigated the expression of chemokines and their receptors in leprosy skin lesions using immunohistochemistry. Skin biopsies from 25 leprosy patients across the leprosy spectrum, 11 patients undergoing type I reversal reactions and four normal donors were immunostained by ABC peroxidase method using antibodies against CC and CXC chemokines and their receptors. Using an in situ hybridization technique we have also studied the expression of monocyte chemoattractant protein 1 (MCP-1), RANTES and interleukin (IL)-8 chemokines mRNA in leprosy skin lesions. Chemokines and receptor expression was detected in all leprosy skin biopsies. Expression of CC chemokines MCP-1 (P < 0.01) and RANTES (P < 0.01) were elevated significantly in borderline tuberculoid leprosy in reversal reaction compared to non-reactional borderline tuberculoid leprosy, but there was no difference in the expression of IL-8 chemokine. Surprisingly, there was no significant difference in the expression of CC (CCR2 and CCR5) and CXC (CXCR2) chemokine receptors across the leprosy spectrum. Similarly, there was no significant difference in the expression of mRNA for MCP-1, regulated upon activation normal T cell expressed and secreted (RANTES) and IL-8 chemokines. Here, the presence of a neutrophil chemoattractant IL-8 in leprosy lesions, which do not contain neutrophils, suggests strongly a role of IL-8 as a monocyte and lymphocyte recruiter in leprosy lesions. These results suggest that the chemokines and their receptors, which are known to chemoattract T lymphocytes and macrophages, are involved in assembling the cellular infiltrate found in lesions across the leprosy spectrum.     

Campylobacter jejuni-mediated induction of CC and CXC chemokines and chemokine receptors in human dendritic cells

Campylobacter jejuni is a leading worldwide bacterial cause of human diarrheal disease. Although the specific molecular mechanisms of C. jejuni pathogenesis have not been characterized in detail, host inflammatory responses are thought to be major contributing factors to the resulting typical acute colitis. The intestinal mucosal chemokine response is particularly important in the initial stages of bacterium-induced gut inflammation. Chemokines attract blood phagocytes and lymphocytes to the site of infection and regulate immune cell maturation and the development of localized lymphoid tissues. The production of chemokines by dendritic cells (DCs) following Campylobacter infection has not yet been analyzed. In the current study, we infected human monocyte-derived DCs with C. jejuni to examine the production of key proinflammatory chemokines and chemokine receptors. The chemokines, including CC families (macrophage inflammatory protein 1α [MIP-1α], MIP-1β, RANTES) and CXC families (growth-related oncogene α [GRO-α], IP-10, and monokine induced by gamma interferon [MIG]), were upregulated in Campylobacter-infected DCs. Chemokine receptors CCR6 and CCR7, with roles in DC trafficking, were also induced in Campylobacter-infected DCs. Further, Campylobacter infection stimulated the phosphorylation of P38, P44/42, and stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) mitogen-activated protein kinases (MAPKs) in DCs. NF-κB activation was specifically involved in chemokine induction in DCs infected with C. jejuni. Additionally, STAT3 was significantly increased in Campylobacter-infected DCs compared to that in uninfected DCs. These results suggest that DCs play a significant role in the initiation and modulation of the inflammatory response by enlisting monocytes, neutrophils, and T lymphocytes during human intestinal infection with Campylobacter.     

Mechanisms of leukocyte trafficking in allergic diseases: insights into new therapies targeting chemokines and chemokine receptors

Marked inflammatory infiltration by activated leukocytes is a characteristic feature of allergic diseases. Elucidation of the mechanisms of leukocyte trafficking in allergic diseases would identify targets to establish novel anti-inflammatory strategies for treatment of these diseases. Leukocyte trafficking is controlled by tissue-specific expression of chemokines and chemokine receptor expression on the leukocyte surface. Here, we review the role of chemokines and their receptors in leukocyte trafficking to inflammatory sites in allergic diseases and discuss therapeutic strategies targeting chemokine networks for treatment of these diseases.     

TNF-alpha microinjection upregulates chemokines and chemokine receptors in the central nervous system without inducing leukocyte infiltration.

Chemokines (chemoattractant cytokines) are key players in the initiation of inflammatory cell accumulation in the central nervous system (CNS). Mechanisms leading to upregulation of chemokines in CNS pathologic conditions remain largely unknown. Numerous in vitro studies showed that inflammatory cytokines stimulate cultured CNS cells to produce chemokines. The main goal of this study was to analyze if an individual proinflammatory cytokine is sufficient to upregulate the chemokine system in the adult CNS in vivo. We analyzed CC chemokine ligand and receptor expression in brains from two different strains of mice (SJL and BALB) after stereotaxic, intracerebral injection of tumor necrosis factor-alpha (TNF-alpha). In both strains, we detected similarly increased expression of chemokines RANTES/CCL5, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4, and MIP-2, as well as chemokine receptors CCR1, CCR2, and CCR5. Interestingly, we did not observe parenchymal leukocyte infiltrates after local TNF-alpha delivery. This observation shows that upregulation of chemokines by TNF-alpha is not sufficient to cause accumulation of leukocytes in the CNS parenchyma in both strains of mice.