RESUMO
The biology of chemokines and their receptors have been linked to the development of chronic allograft damage. Effects of CCR1 antagonist BX 471 were studied in a Fischer to Lewis renal transplantation model at days 10, 21 and 42 after transplantation. BX 471 treatment did not effectively reduce signs of acute rejection at day 10 but significantly improved allograft function and morphology at day 21 posttransplantation. When therapy was initiated on day 21 after transplantation, glomerulosclerosis and tubulointerstitial fibrosis were significantly inhibited by day 42 posttransplantation. Parallel decrease in infiltrating and proliferating mononuclear cells (ED1, CD8 and Ki67) was observed in treated allografts. Expression of acute phase reactive and proinflammatory genes (HO-1, osteopontin) and molecules associated with fibrosis (PAI-1, TGF-beta1, biglycan) was downregulated at day 21; reduced collagen deposition was observed, parallel to a significant lower number of alpha-SMA+ interstitial myofibroblasts. In situ hybridization demonstrated that biglycan expression was reduced following CCR1 blockade in interstitium of treated allografts. CCR1 antagonism was found to inhibit CCL5-induced secretion of biglycan by macrophages in vitro. CCR1 blockade significantly inhibited development and progression of chronic allograft damage. CCR1 antagonists may represent a therapeutic option for chronic inflammation and fibrosis in renal grafts.
Assuntos
Rejeição de Enxerto/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , Transplante de Rim , Compostos de Fenilureia/uso terapêutico , Piperidinas/uso terapêutico , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Biglicano , Progressão da Doença , Proteínas da Matriz Extracelular/antagonistas & inibidores , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fibrose , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Falência Renal Crônica/patologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Modelos Animais , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Proteoglicanas/antagonistas & inibidores , Proteoglicanas/genética , Proteoglicanas/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Receptores CCR1 , Linfócitos T/efeitos dos fármacosAssuntos
Leucócitos Mononucleares/metabolismo , Esclerose Múltipla/metabolismo , Fagócitos/metabolismo , Receptores CCR5/biossíntese , Receptores de Quimiocinas/biossíntese , Adulto , Autopsia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Receptores CCR1 , Receptores CCR8Assuntos
Quimiocinas/antagonistas & inibidores , Imunossupressores/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Quimiocinas/imunologia , Quimiocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunossupressores/química , Imunossupressores/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismoAssuntos
Sistema Nervoso Central/metabolismo , Esclerose Múltipla/metabolismo , Fagócitos/metabolismo , Receptores de Quimiocinas/biossíntese , Adulto , Idoso , Diferenciação Celular , Núcleo Celular/metabolismo , Células Cultivadas , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Receptores CCR1 , Receptores CCR5/biossínteseRESUMO
Chemokines help control normal leukocyte trafficking as well as their infiltration into tissues during acute and chronic inflammation. Matrix metalloproteinases (MMPs) help support the extravasation and infiltration of leukocytes through limited proteolysis of basement membranes and matrix material. The effect of the chemokines RANTES/CCL5, MCP-1/CCL and SDF-1/CXCL12 on secretion of the matrix metalloproteinase B and its endogenous inhibitor TIMP-1 was studied. RANTES/CCL5 and SDF-1/CXCL12 were found to induce MMP-9 secretion in primary human monocytes while TIMP-1 secretion was not affected. RANTES/CCL5 effects were mediated through CCR1 because the CCR1 antagonist BX471 was found to effectively block RANTES/CCL5-induced MMP-9 secretion.
Assuntos
Quimiocinas/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Monócitos/metabolismo , Quimiocinas/administração & dosagem , Humanos , Técnicas In Vitro , Monócitos/enzimologiaRESUMO
Mononuclear phagocytes (monocytes, macrophages, and microglia) are considered central to multiple sclerosis (MS) pathogenesis. Molecular cues that mediate mononuclear phagocyte accumulation and activation in the central nervous system (CNS) of MS patients may include chemokines RANTES/CCL5 and macrophage inflammatory protein-1alpha/CCL3. We analyzed expression of CCR1 and CCR5, the monocyte receptors for these chemokines, on circulating and cerebrospinal fluid CD14+ cells, and in MS brain lesions. Approximately 70% of cerebrospinal fluid monocytes were CCR1+/CCR5+, regardless of the presence of CNS pathology, compared to less than 20% of circulating monocytes. In active MS lesions CCR1+/CCR5+ monocytes were found in perivascular cell cuffs and at the demyelinating edges of evolving lesions. Mononuclear phagocytes in early demyelinating stages comprised CCR1+/CCR5+ hematogenous monocytes and CCR1-/CCR5- resident microglial cells. In later stages, phagocytic macrophages were uniformly CCR1-/CCR5+. Cultured in vitro, adherent monocytes/macrophages up-regulated CCR5 and down-regulated CCR1 expression, compared to freshly-isolated monocytes. Taken together, these findings suggest that monocytes competent to enter the CNS compartment derive from a minority CCR1+/CCR5+ population in the circulating pool. In the presence of ligand, these cells will be retained in the CNS. During further activation in lesions, infiltrating monocytes down-regulate CCR1 but not CCR5, whereas microglia up-regulate CCR5.
Assuntos
Sistema Nervoso Central/patologia , Esclerose Múltipla/patologia , Fagócitos/metabolismo , Fagócitos/patologia , Receptores CCR5/metabolismo , Receptores de Quimiocinas/metabolismo , Adulto , Diferenciação Celular , Células Cultivadas , Sistema Nervoso Central/metabolismo , Líquido Cefalorraquidiano/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/metabolismo , Esclerose Múltipla/metabolismo , Bainha de Mielina/patologia , Receptores CCR1RESUMO
Although chemokines were originally defined as host defense proteins it is now clear that their repertoire of functions extend well beyond this role. For example chemokines such as MGSA have growth regulatory properties while members of the CXC chemokine family can be mediators or inhibitors of angiogenesis and may be important targets for oncology. Recent work shows that the chemokine receptor CXCR4 and its cognate ligand SDF play important roles in the development of the immune, circulatory and central nervous systems. In addition, chemokine receptors play an important role in the pathogenesis of the AIDS virus, HIV-1. Taken together these findings expand the biological importance of chemokines from that of simple immune modulators to a much broader biological role than was at first appreciated and these and other properties of the chemokine receptor family are discussed in detail in this review.
Assuntos
Receptores de Quimiocinas/química , Receptores de Quimiocinas/fisiologia , Sequência de Aminoácidos , Animais , Quimiocinas C/metabolismo , Quimiocinas CC/metabolismo , Quimiocinas CXC/metabolismo , Humanos , Dados de Sequência Molecular , Alinhamento de SequênciaRESUMO
The classic signs of acute cellular rejection during organ transplantation include the infiltration of mononuclear cells into the interstitium. This recruitment of leukocytes into the transplanted tissue is promoted by chemokines like RANTES. Since RANTES is a potent agonist for the CC chemokine receptor CCR1, we examined whether the CCR1 antagonist BX 471 was efficacious in a rabbit kidney transplant rejection model. BX 471 was able to compete with high affinity with the CCR1 ligands MIP-1alpha and RANTES for binding to HEK 293 cells expressing rabbit CCR1. BX 471 was a competitive antagonist of rabbit CCR1 in Ca(2+) flux studies. Two separate studies in which animals were subcutaneously implanted with slow release pellets of BX 471 demonstrated that animals implanted with BX 471 had increased survival compared with untreated controls or animals implanted with placebo. The mean survival time for the placebo group was 12.33+/-1.7 days. The animals in the BX 471 treated group had mean survival times of 16.9+/-2.1 and 16.0+/-1.7 days, respectively, for the two studies. Analysis of the combined data by Student t-test gave a P value of 0.03 that is significant at the 0.05 level. In addition, there was a marked reduction in the urea and creatinine levels in the BX 471 treated animals compared with the control and placebo groups in both studies. Finally, pathologic analysis of the kidneys in the rabbit renal transplantation model from animals in the different groups showed that BX 471 was similar to cyclosporin in its ability to prevent extensive infarction of transplanted kidneys. Based on the data from these studies, BX 471 shows clear efficacy at the single dose tested compared with animals treated with placebo.
Assuntos
Rejeição de Enxerto , Transplante de Rim , Compostos de Fenilureia/metabolismo , Piperidinas/metabolismo , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Linhagem Celular , Quimiocina CCL3 , Quimiocina CCL4 , Creatinina/sangue , Modelos Animais de Doenças , Sobrevivência de Enxerto , Humanos , Células Jurkat , Proteínas Inflamatórias de Macrófagos/metabolismo , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Coelhos , Receptores CCR1 , Transplante Homólogo , Ureia/sangueRESUMO
Chemokines and their receptors control the emigration of leukocytes during inflammation. The role of the RANTES (regulated on activation normal T-cell expressed and secreted) receptors CCR1 and CCR5 in the selective recruitment of monocytes, T(H)1-like T-cell clones, and peripheral T cells enriched for CD45RO(+) "memory" cells were tested in a system in which arrest under flow conditions is triggered by RANTES immobilized to activated endothelium. With the use of selective nonpeptide receptor antagonists or blocking antibodies, it was found that the RANTES-induced arrest of these cells was mediated predominantly by CCR1. In contrast, CCR5 mainly contributed to the spreading in shear flow, and both CCR1 and CCR5 supported transendothelial chemotaxis toward RANTES. The data in this study reveal specialized roles of apparently redundant receptors in distinct steps of leukocyte trafficking and suggest that not all receptors currently used to define mononuclear cell subsets are involved in their direct recruitment from the circulation.
Assuntos
Quimiocina CCL5/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Proteínas Inflamatórias de Macrófagos/farmacologia , Receptores CCR5/fisiologia , Receptores de Quimiocinas/fisiologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL4 , Técnicas de Cocultura , Endotélio Vascular/citologia , Citometria de Fluxo , Hemorreologia , Humanos , Memória Imunológica , Molécula 1 de Adesão Intercelular/metabolismo , Receptores CCR1 , Receptores CCR5/genética , Receptores de Quimiocinas/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade por Substrato , Subpopulações de Linfócitos T/citologia , Células Th1/citologiaRESUMO
Chemokines like RANTES appear to play a role in organ transplant rejection. Because RANTES is a potent agonist for the chemokine receptor CCR1, we examined whether the CCR1 receptor antagonist BX471 is efficacious in a rat heterotopic heart transplant rejection model. Treatment of animals with BX471 and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself ineffective in prolonging transplant rejection, is much more efficacious in prolonging transplantation rejection than animals treated with either cyclosporin or BX471 alone. We have examined the mechanism of action of the CCR1 antagonist in in vitro flow assays over microvascular endothelium and have discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelium. Together, these data demonstrate a significant role for CCR1 in allograft rejection.
Assuntos
Rejeição de Enxerto , Transplante de Coração , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Linhagem Celular , Ciclosporina/administração & dosagem , Sobrevivência de Enxerto , Humanos , Masculino , Ratos , Ratos Endogâmicos Lew , Receptores CCR1 , Receptores de Quimiocinas/fisiologiaRESUMO
APJ is a seven transmembrane domain G-protein-coupled receptor that functions as a coreceptor for some primate immunodeficiency virus strains. The in vivo significance of APJ coreceptor function remains to be elucidated, however, due to the lack of an antibody that can be used to assess APJ expression, and because of the absence of an antibody or ligand that can block APJ coreceptor activity. Therefore, we produced a specific monoclonal antibody (MAb 856) to APJ and found that it detected this receptor in FACS, immunofluorescence, and immunohistochemistry studies. MAb 856 also recognized APJ by Western blot, enabling us to determine that APJ is N-glycosylated. Using this antibody, we correlated APJ expression with coreceptor activity and found that APJ had coreceptor function even at low levels of expression. However, we found that APJ could not be detected by FACS analysis on cell lines commonly used to propagate primate lentiviruses, nor was it expressed on human PBMC cultured under a variety of conditions. We also found that some viral envelope proteins could mediate fusion with APJ-positive, CD4-negative cells, provided that CD4 was added in trans. These findings indicate that in some situations APJ use could render primary cell types susceptible to virus infection, although we have not found any evidence that this occurs. Finally, the peptide ligand for APJ, apelin-13, efficiently blocked APJ coreceptor activity.
Assuntos
Receptores de Dopamina D2/fisiologia , Receptores Acoplados a Proteínas G , Receptores de HIV/fisiologia , Adipocinas , Animais , Anticorpos Monoclonais/imunologia , Apelina , Receptores de Apelina , Proteínas de Transporte/metabolismo , Linhagem Celular , Antagonistas dos Receptores de Dopamina D2 , HIV-1/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos BALB C , Primatas , Receptores de Dopamina D2/biossíntese , Receptores de Dopamina D2/imunologia , Receptores de HIV/biossíntese , Receptores de HIV/imunologia , Receptores Virais/biossíntese , Receptores Virais/imunologia , Receptores Virais/fisiologia , Vírus da Imunodeficiência Símia/metabolismo , Linfócitos T/imunologia , TransfecçãoRESUMO
Chemokine receptors comprise a large family of seven transmembrane domain G protein-coupled receptors differentially expressed in diverse cell types. Biological activities have been most clearly defined in leukocytes, where chemokines coordinate development, differentiation, anatomic distribution, trafficking, and effector functions and thereby regulate innate and adaptive immune responses. Pharmacological analysis of chemokine receptors is at an early stage of development. Disease indications have been established in human immunodeficiency virus/acquired immune deficiency syndrome and in Plasmodium vivax malaria, due to exploitation of CCR5 and Duffy, respectively, by the pathogen for cell entry. Additional indications are emerging among inflammatory and immunologically mediated diseases, but selection of targets in this area still remains somewhat speculative. Small molecule antagonists with nanomolar affinity have been reported for 7 of the 18 known chemokine receptors but have not yet been studied in clinical trials. Virally encoded chemokine receptors, as well as chemokine agonists and antagonists, and chemokine scavengers have been identified in medically important poxviruses and herpesviruses, again underscoring the importance of the chemokine system in microbial pathogenesis and possibly identifying specific strategies for modulating chemokine action therapeutically. The purpose of this review is to update current concepts of the biology and pharmacology of the chemokine system, to summarize key information about each chemokine receptor, and to describe a widely accepted receptor nomenclature system, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area.
Assuntos
Farmacologia/normas , Receptores de Quimiocinas/classificação , Terminologia como Assunto , Animais , Humanos , Receptores de Quimiocinas/efeitos dos fármacos , Receptores de Quimiocinas/genéticaRESUMO
Chemokines belong to a large family of chemoattractant molecules involved in the directed migration of immune cells. They achieve their cellular effects by direct interaction with cell surface receptors. Chemokines appear to be involved in a variety of proinflammatory and autoimmune diseases and this makes them and their receptors very attractive therapeutic targets. This review highlights current efforts toward obtaining highly specific chemokine receptor antagonists and discusses their chemistry and potential role as disease modifiers.
Assuntos
Receptores de Quimiocinas/antagonistas & inibidores , Arteriosclerose/fisiopatologia , Doenças Autoimunes/fisiopatologia , Quimiocinas/fisiologia , Humanos , Transplante de Órgãos , Dermatopatias/fisiopatologiaRESUMO
The species specificity of a small molecule antagonist for the human CCR1 chemokine receptor, 2-2-diphenyl-5-(4-chlorophenyl)piperidin-1-yl)valeronitrile (CCR1 antagonist 1), has been examined using cloned CCR1 receptors from various species. The compound was able to bind to rabbit, marmoset, and human CCR1, and was able to block the functional activation of these receptors. However, it failed to significantly displace radiolabeled macrophage inflammatory protein-1alpha (MIP-1alpha) binding to mouse CCR1 at concentrations up to 10 microM. These data suggested that the antagonist binding site is well-conserved in rabbit, marmoset and human CCR1, but not in mouse CCR1. The functional selectivity and mechanism of action for CCR1 antagonist 1 were further characterized. CCR1 antagonist 1 blocked the increase in intracellular Ca(2+) stimulated by CCR1 agonists, but had no effect on N-formyl-Met-Leu-Phe (FMLP), monocyte chemotactic protein-1 (MCP-1) and stromal-derived factor 1alpha (SDF1alpha)-induced Ca(2+) mobilization, demonstrating functional selectivity for CCR1. Since CCR1 antagonist 1 is a functional antagonist of marmoset and rabbit CCR1 receptors, it should be possible to test its efficacy in animal models of disease.
Assuntos
Nitrilas/farmacologia , Piperazinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cálcio/metabolismo , Callithrix , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CCL5/metabolismo , Clonagem Molecular , DNA Complementar/genética , DNA Complementar/metabolismo , Humanos , Proteínas Inflamatórias de Macrófagos/metabolismo , Camundongos , Dados de Sequência Molecular , Nitrilas/toxicidade , Piperazinas/toxicidade , Piperidinas/farmacologia , Piperidinas/toxicidade , Coelhos , Receptores CCR1 , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/fisiologia , Especificidade da EspécieRESUMO
It has been shown that deletion of the chemokine receptor, CXCR4, causes disordered angiogenesis in mouse models. In the present studies, we examined the distribution and trafficking of CXCR4 in human endothelial cells, tested their responses to the CXCR4 ligand, SDF-1, and asked whether endothelial cell CXCR4 can serve as a cell surface receptor for the binding of viruses. The results show that CXCR4 is present on endothelial cells from coronary arteries, iliac arteries and umbilical veins (HUVEC), but expression was heterogeneous, with some cells expressing CXCR4 on their surface, while others did not. Addition of SDF-1 caused a rapid decrease in CXCR4 surface expression. It also caused CXCR4-mediated activation of MAPK, release of PGI(2), endothelial migration, and the formation of capillary-like structures by endothelial cells in culture. Co-culture of HUVEC with lymphoid cells that were chronically infected with a CD4-independent/CXCR4-tropic variant of HIV-2 resulted in the formation of multinucleated syncytia. Formation of the syncytia was inhibited by each of several different CXCR4 antibodies. Thus, our findings indicate: (1) that CXCR4 is widely expressed on human endothelial cells; (2) the CXCR4 ligand, SDF-1, can evoke a wide variety of responses from human endothelial cells; and (3) CXCR4 on endothelial cells can serve as a receptor for isolates of HIV that can utilize chemokine receptors in the absence of CD4.
Assuntos
Endotélio Vascular/metabolismo , HIV-2/fisiologia , Receptores CXCR4/fisiologia , Fármacos Anti-HIV/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Capilares/citologia , Fusão Celular/efeitos dos fármacos , Quimiocina CXCL12 , Quimiocinas CXC/farmacologia , Quimiotaxia/efeitos dos fármacos , Colágeno , Vasos Coronários/citologia , Efeito Citopatogênico Viral/efeitos dos fármacos , Regulação para Baixo , Combinação de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/virologia , Epoprostenol/metabolismo , Citometria de Fluxo , Expressão Gênica , Humanos , Artéria Ilíaca/citologia , Técnicas Imunoenzimáticas , Laminina , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microscopia de Fluorescência , Morfogênese/efeitos dos fármacos , Proteoglicanas , Receptor Cross-Talk , Receptor PAR-1 , Receptores CXCR4/genética , Receptores de Trombina/fisiologia , Acetato de Tetradecanoilforbol/farmacologia , Veias Umbilicais/citologiaRESUMO
Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.
Assuntos
Anti-Inflamatórios/síntese química , Nitrilas/síntese química , Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Cálcio/metabolismo , Linhagem Celular , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CCL5/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas Inflamatórias de Macrófagos/metabolismo , Proteínas Inflamatórias de Macrófagos/farmacologia , Nitrilas/química , Nitrilas/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Receptores CCR1 , Receptores de Quimiocinas/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
A decade ago several new cytokines were described that orchestrated the activation and migration of immune cells. These newly described cytokines, of which interleukin-8 (IL-8) was a representative member, defined a novel group of molecules called chemokines (chemotactic cytokines). Chemokines are low molecular weight, 8-12 kDa, basic proteins that have been classified into four distinct families, CXC, CC, C and CX3C, based on the position of their first two conserved cysteine residues. The expression and biological function of chemokines along with their cognate receptors have been well described on various subsets of leukocytes. Only more recently have these molecules been described on various cells within the central nervous system. These pro-inflammatory proteins have been implicated in a variety of diseases within the central nervous system from Multiple Sclerosis to AIDS dementia. While chemokines are likely to enhance the evolution of central nervous system inflammatory disorders they also have other roles in normal brain function and development. This review summarizes the role of chemokines and their receptors in the normal and pathophysiological brain.
Assuntos
Sistema Nervoso Central/metabolismo , Quimiocinas/fisiologia , Receptores de Quimiocinas/fisiologia , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/metabolismo , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Movimento Celular , Sistema Nervoso Central/imunologia , Quimiocinas/imunologia , Endotélio/citologia , Endotélio/metabolismo , Humanos , Microglia/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Neurônios/metabolismo , Receptores de Quimiocinas/imunologiaRESUMO
Chemokines mediate their effects by binding to cell-surface receptors that belong to the seven-transmembrane-domain superfamily of proteins. Chemokine receptors have been subject to intense scrutiny following the recent discovery that several of them are co-receptors for HIV-1. Here, Richard Horuk reviews the latest developments in chemokine receptor research with a particular focus on their role as HIV-1 co-receptors.
Assuntos
HIV-1/fisiologia , Receptores de Quimiocinas/fisiologia , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Antígenos CD4/genética , Antígenos CD4/fisiologia , Linfócitos T CD4-Positivos/virologia , Quimiocinas/fisiologia , Progressão da Doença , Regulação da Expressão Gênica , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/terapia , Infecções por HIV/virologia , HIV-1/classificação , Macaca mulatta , Substâncias Macromoleculares , Macrófagos/virologia , Dados de Sequência Molecular , Vírus da Raiva , Receptores CCR2 , Receptores CCR5/química , Receptores CCR5/genética , Receptores CCR5/fisiologia , Receptores CXCR4/química , Receptores CXCR4/genética , Receptores CXCR4/fisiologia , Receptores de Quimiocinas/química , Receptores de Quimiocinas/genética , Receptores de Citocinas/química , Receptores de Citocinas/genética , Receptores de Citocinas/fisiologia , Proteínas Recombinantes de Fusão/metabolismo , Relação Estrutura-Atividade , Vírus da Estomatite Vesicular IndianaRESUMO
Chemokines belong to a large family of chemoattractant molecules involved in the directed migration of immune cells. They achieve their cellular effects by direct interaction with cell surface receptors. One such chemokine receptor is CCR1 which is particularly responsive to the C-C chemokines RANTES and MIP-1alpha. This review seeks to highlight the biology, molecular biology, physiology and pathophysiology of CCR1 and looks at the potential of this receptor as a therapeutic target in autoimmunity and inflammation. In addition, current progress in the discovery and development of CCR1 antagonists is summarized.
RESUMO
Melanoma growth stimulating activity (MGSA) and IL-8 are related chemokines that are potent chemoattractants and activators of neutrophils both in vitro and in vivo. Increasing evidence suggests that these molecules play an important role in inflammation; thus, antagonists of their action could be useful therapeutically as antiinflammatory agents. We have generated an MGSA mutant, H19A, that shows a dissociation between receptor binding and biologic activity. The biologic activity of the H19A mutant is between 133-fold and 282-fold less potent than that of wild-type MGSA measured by three independent assays of neutrophil function, i.e., elastase release chemotaxis and the up-regulation of CD18. In addition, pretreatment of cells with the H19A mutant inhibited the ability of MGSA to induce elastase release and chemotaxis and to increase intracellular calcium. However, competition binding studies in cells transfected with the CXCR2 receptor and in neutrophils demonstrate that the receptor affinity of the H19A mutant is only 13-fold less than that of wild-type MGSA. These studies suggest that the mutant MGSA is defective in activating signaling through the receptor and indicate that binding to the receptor is not sufficient to activate a biologic response. The dissociation between receptor binding and activation for this mutant suggests that it should be possible to design antagonists of MGSA that may be of clinical utility.