摘要:

AbstractRheumatoid arthritis (RA) is an autoimmune disease characterized by the elicitation and activation of a number of leukocyte populations within both the synovial space and joint tissue. The recruited leukocytes subsequently play an instrumental role in synovial cell proliferation, pannus formation, and bone erosion. Although it is known that leukocytes are important participants in the evolving joint pathology, the mechanism responsible for the successful elicitation of cells to the joint is not clear. A number of studies have identified an association of specific cytokines, including chemokines, with active arthritis, but longitudinal analyses of cytokine expression and the causal role of these mediators have not been defined. Animal models and cell culture systems have proved useful in identifying the expression of various cytokines during the maintenance of chronic joint inflammation. In addition, animal models have provided important information regarding the kinetic production and contribution of specific mediators to the development of experimental arthritis. These studies provide insight into the potential mechanisms for leukocyte involvement in inflammatory joint disease.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.6

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractAllergic airway inflammation is characterized by peribronchial eosinophil accumulation within the submucosa surrounding the airway. The initial induction of immunoglobulin E (IgE)‐mediated mast cell degranulation, up‐regulation of adhesion molecules, and the production of inflammatory and chemotactic cytokines, leading to the infiltration of specific leukocyte subsets, is orchestrated in a sequential manner. The activation and degranulation of local mast cell populations is an immediate airway response mediated both by antigen‐specific, surface bound IgE and by cytokine‐induced activational pathways. Subsequently the infiltration and activation of effector leukocytes (neutrophils and eosinophils) mediated by the persistant activation of allergen‐specific T cells leads to pathological manifestations within the lung and airway. The development of appropriate animal models to dissect the critical mechanisms involved in antigen‐induced airway pathology is crucial for the development of efficacious therapies. We have utilized a model of allergic airway inflammation induced by intratracheal challenge with parasite (Schistosoma mansoni) egg antigen in presensitized mice. This model has proven useful in the assessment of eosinophil recruitment and has identified key cytokines involved in leukocyte elicitation. These cytokines include interleukin‐4 and tumor necrosis factor, which appear to act as early response mediators, as well as C‐C chemokines, macrophage inflammatory protein‐1a, and RANTES, which act directly on eosinophil recruitment. In addition, we have found that both C‐X‐C and C‐C chemokines are expressed in pulmonary‐derived mast cells, suggesting an important contribution to leukocyte responses in the allergic airway.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.13

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractChemokines are relatively small peptides with potent chemoattractant and activation activities for leukocytes. Several chemokine receptors have been cloned and characterized and all are members of the G protein‐coupled receptor superfamily. Using degenerate oligonucleotides and polymerase chain reaction, we have identified seven novel receptors with significant homology to chemokine receptors. Two of these sequences are presented here for the first time. We have shown, with gene mapping studies, that receptors with the highest sequence similarity are closely linked on human chromosomes. This close genetic association suggests a functional relationship as well.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.18

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractEffective host defense against bacterial invasion is characterized by the vigorous recruitment and activation of inflammatory cells, which is dependent on the coordinated expression of both pro‐and anti‐inflammatory cytokines. In this review, we present evidence indicating that both C‐X‐C and C‐C chemokines are integral components of antibacterial host defense. Specifically, in vitro studies indicate that C‐X‐C chemokines [interleukin‐8 (IL‐8) and macrophage inflammatory protein 2 (MIP‐2)] and the C‐C chemokine macrophage inflammatory protein 1 alpha (MIP‐1α) augment the ability of polymorphonuclear leukocytes (PMNs) and alveolar macrophages, respectively, to phagocytose and killEscherichia coli.In addition, the intratracheal instillation ofKlebsiella pneumoniaein CD‐I mice results in time‐dependent production of MIP‐2 and MIP‐1α, and the inhibition of MIP‐2 bioactivity in vivo results in decreases in lung PMN influx, impaired bacterial clearance, and early mortality. Finally, the anti‐inflammatory cytokine interleukin‐10 (IL‐10) is also expressed within the lung during the evolution ofKlebsiellapneumonia, and neutralization of IL‐10 in vivo results in enhanced proinflammatory cytokine production, bacterial clearance, and increases in both short‐ and long‐term survival. In conclusion, our studies indicate that specific chemokines are important mediators of leukocyte recruitment and/or activation in bacterial pneumonia and that the expression of these chemokines is regulated by endogenously produced IL‐10.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.24

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractThe Duffy antigen receptor for chemokines (DARC) is expressed in human erythrocytes and on endothelial cells lining postcapillary venules in kidney and spleen. DARC is a promiscuous chemokine receptor and a binding protein for the malarial parasitePlasmodium vivax.The expression of DARC by subsets of endothelial cells and neurons in discrete anatomic sites in the brain suggests that this enigmatic receptor may have multiple roles in normal and pathological physiology. Conservation of this promiscuous chemokine binding function is evident from the similarity in nucleotide sequence of DARC homologues from multiple species, as well as the high‐affinity binding of human chemokines to murine and avian erythrocytes. Analysis of the functional domains of DARC using chimeric receptors and monoclonal antibodies to multiple extracellular domains localized chemokine binding to structures in the amino terminal extracellular domain (E1). Scatchard analysis demonstrated that a chimeric DARC receptor, composed of the E1 domain of DARC and the predicted hydrophobic helices and loops of interleukin‐8RB (IL‐8RB), bound IL‐8, and MGSA withKDvalues almost identical to the wild type receptors and bound a repertoire of C‐X‐C and C‐C chemokines characteristic of DARC. Although numerous reports have demonstrated that chemokines such as IL‐8 are expressed in the brain, presumably by glial cells, little insight into the nature of their role in normal or pathological physiology in the nervous system has developed because the target cells that express the corresponding receptors have not yet been identified. Northern blotting experiments suggest that mRNA encoding DARC are expressed in the central nervous system, however, interpretation of this is unclear because of the ubiquitous expression of DARC lining postcapillary venules. This study provides direct evidence to localize expression of DARC in the cental nervous system. Immunohistochemical examination of human archival sections of the brain with monoclonal antibodies specific for DARC localize expression of DARC to cell bodies and processes of Purkinjie cells in the cerebellum. The immunohistochemical findings were supported by analysis of chemokine binding and radioligand crosslinking with membranes made from various brain fractions. The hierarchical expression of DARC in neurons in the cerebellum suggests that chemokines may play an important role in the modulation of neuronal activity by glial cells.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.29

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractChemolrines have been convincingly implicated in driving leukocyte emigration in different inflammatory reactions. However, the cellular and molecular mechanisms of chemokine involvement in leukocyte emigration are not yet clear. We and others suggested that leukocyte adhesion to the endothelium and transmigration are induced by chemokines immobilised on the endothelial cell surface. This would require the presence of specific chemokine binding sites in this microanatomical location. Using an in situ binding assay we demonstrated the presence of binding sites for interleukin‐8 (IL‐8) and RANTES, but not monocyte inflammatory protein‐1α on the endothelium of postcapillary venules and small veins in human skin. In contrast, venules and veins in various anatomical locations showed dramatically differing IL‐8 binding patterns. The subcellular distribution of IL‐8 in the venular endothelial cells following its in vivo and ex vivo injections was studied by use of electron microscopy. Our results suggest that IL‐8 was internalized by the endothelial cells, transported transcellularly via plasmalemmal vesicles, and released onto the luminal surface where it appeared located preferentially on tips of membrane protrusions. We were unable to study the endothelial IL‐8 binding or transport in vitro because all the in vitro propagated endothelial cell lines and primary endothelial cells tested lacked IL‐8 binding sites. This includes human umbilical vein endothelial cells (HUVECs), which also did not bind IL‐8 in situ. However, HUVECs provided a satisfactory in vitro system to study the secretion of IL‐8 by the endothelial cells. Two possible alternative pathways were described: secretion directly from the Golgi apparatus or following storage in Weibel‐Palade bodies.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.39

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractChemokines are cytokines capable of inducing Chemotaxis of inflammatory cells in vitro. It is likely that they are also involved in controlling cell migration in vivo, but this and other putative functions have not been properly validated to date. To investigate these functions in vivo, a number of new experimental approaches are required. This mini‐review focuses on a set of genetic approaches that can be used to understand chemokine function at the level of the organism. Hopefully, these approaches will help us define the fundamental role of chemokines in development, homeostasis, and disease.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.45

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractIn the dermal sites of atopic skin, eosinophil (Eo) granule protein or more rarely intact Eos represent a characteristic histological feature. We addressed the question of whether lesional scales of patients with various eosinophilic skin disorders contain Eo attractant and tried to characterize it biochemically. In scales of a patient with drug reaction, heparin‐binding Eo attractants could be identified. High‐performance liquid chromatographic analyses together with specific ELISA and Western blot analyses revealed identity with RANTES. No other heparin‐binding Eo chemotaxin could be identified. HPLC analysis of pooled lesional scale extracts of patients with atopic dermatitis showed fractions containing only weak heparin‐binding Eo‐chemotactic activity, which, however, showed RANTES immunoreactivity. In experiments to elucidate the putative cellular origin of Eo‐attracting chemokines in human skin we investigated supernatants of atopic skin–derived T lymphocytes as well as supernatants of stimulated dermal fibroblasts for Eo‐chemotactic factors. Unexpectedly, we did not find any heparin‐bound Eo attractants in supernatants of stimulated cultured atopic skin–derived T lymphocyte clones, whereas fibroblasts produced RANTES as well as granulocyte‐macrophage colony‐stimulating factor. Therefore, fibroblasts are a likely source of eosinophil attractant cells, which could contribute to the Eo infiltrate. Selectivity of the infiltrate might come from selective induction of RANTES and/or induction of other as yet unidentified Eo‐specific chemokines.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.51

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractThe chemokine superfamily can be sub‐divided into two groups based on their amino terminal cysteine spacing. The CXC chemokines are primarily involved in neutrophil‐mediated inflammation and, so far, two human receptors have been cloned. The CC chemokines tend to be involved in chronic inflammation, and recently we have cloned a fourth leukocyte receptor for this group of ligands. Understanding what makes one receptor bind its range of agonists is important if we are to develop potent selective antagonists. We have started to investigate the molecular basis of this receptor selectivity by looking at why CC chemokines do not bind to the CXC receptors in several ways. First, we looked at the role of the three‐dimensional structure of the ligand, and have solved the three‐dimensional structure of RANTES using nuclear magnetic resonance spectroscopy. The structure is similar to that already determined for the CC chemokine macrophage inflammatory protein‐1β, and it has a completely different dimer interface to that of the CXC chemokine interleukin‐8 (IL‐8). However, the monomer structures of all the chemokines are very similar, and at physiological concentrations the proteins are likely to be monomeric. Second, by examining all the known CC and CXC chemokines, we have found a region that differs between the two subfamilies. Mutations of one of the residues in this region, Leu‐25 in IL‐8, to tyrosine (which is conserved at this position in CC chemokines) enables the mutant IL‐8 to bind CC‐chemokine receptor‐1 (CC‐CKR‐1) and introduces monocyte chemoattractant activity. Using other mutations in this region, we can show a direct interaction with the N‐terminus of CC‐CKR‐1. Third, we have found that modification of the amino terminus of RANTES by addition of one amino acid makes it into an antagonist with nanomolar potency. Taken together, this data suggests a two‐site model for receptor activation and for selectivity between CC and CXC chemokines, with an initial receptor contact provided by the main body of the chemokine, and activation provided by the amino terminal region.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.53

出版商:Wiley    

年代:1996

数据来源: WILEY

摘要:

AbstractMacrophage inflammatory protein 1α (MIP‐1α) is a member of the C‐C subfamily of chemokines, a large superfamily of low‐molecular‐weight, inducible proteins that exhibit a variety of proinflammatory activities in vitro including leukocyte Chemotaxis. MIP‐1α is a particularly interesting chemokine, because in addition to its proinflammatory activities, it inhibits the proliferation of hematopoietic stem cells in vitro and in vivo. Here, the biologic properties of MIP‐1α are reviewed in light of recent data on mice homozygous for a disruption of the MIP‐1α gene. The MIP‐1α null mice have no overt abnormalities of peripheral blood or bone marrow cells, indicating that MIP‐1α is not necessary for normal hematopoiesis. However, the MIP‐1α null mice have a reduced inflammatory response to influenza virus and are resistant to coxsackievirus‐induced myocarditis. These data demonstrate that MIP‐1α is required for a normal inflammatory response to these viruses. Agents that inhibit the action of MIP‐1α may therefore prove useful for controlling inflammation in these and other settings.

ISSN:0741-5400    

DOI:10.1002/jlb.59.1.61

出版商:Wiley    

年代:1996

数据来源: WILEY