Chemokines in the pathogenesis of liver disease: so many players with poorly defined roles
Kenneth J. SimpsonNeil C. HendersonCynthia L. Bone‐LarsonNicholas W. LukacsCory M. HogaboamSteven L. Kunkel
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Abstract:
Many new chemokines have been described in recent years, resulting in a new classification of these chemoattractant proteins. The characterization of the biological functions of most chemokines relates to their ability to induce chemotaxis in circulating inflammatory cells. However, it is now clear that chemokines have a much wider biological role, including angiogenesis, carcinogenesis and involvement in the pathogenesis of HIV infection. Our understanding of the role of chemokines in the pathogenesis of disorders of the lungs and brain outstrips that with regard to disorders of the liver. An increased understanding of the role of chemokines in the pathogenesis of liver disease may lead to the development of novel therapies for hepatic disease.Keywords:
Pathogenesis
Liver disease
The assembly of chemotaxis receptors and signaling proteins into polar arrays is universal in motile chemotactic bacteria. Comparative genome analyses indicate that most motile bacteria possess multiple chemotaxis signaling systems, and experimental evidence suggests that signaling from distinct chemotaxis systems is integrated. Here, we identify one such mechanism. We show that paralogs from two chemotaxis systems assemble together into chemoreceptor arrays, forming baseplates comprised of proteins from both chemotaxis systems. These mixed arrays provide a straightforward mechanism for signal integration and coordinated response output from distinct chemotaxis systems. Given that most chemotactic bacteria encode multiple chemotaxis systems and the propensity for these systems to be laterally transferred, this mechanism may be common to ensure chemotaxis signal integration occurs.
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Under the influence of environmental chemical substances phagocytes are capable of directed migration towards chemoattractant concentration gradient (chemotaxis) and of increased speed of movement (chemokinesis). In the chain of events "triggered" by inflammation an important role is played by chemotaxis. The content of cell membrane enzymes, the level of cyclic nucleotides, mechanisms of ion transport, and ways of energy production change in response to the chemotaxic factor. Primary (congenital) and secondary (acquired) disorders of chemotaxis are distinguished. In detecting chemotaxis defects it is necessary to determine the capacity of cells for spontaneous migration in the absence of a chemical stimulation as well as the presence of serum inhibitors of chemotaxis. The study of cell receptor apparatus with the help of structurally defined chemotaxic factors as well as of the motor apparatus of the cell will give an insight into the concept of chemotaxis. At the same time, exerting an influence on chemotaxis simultaneously influences the inflammatory processes, therefore new approaches to treatment of inflammatory diseases may be developed by means of drugs modulating chemotaxis.
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Abstract Chemotactic behavior is essential for the survival of animals. However, the mechanism by which animals carry out chemotaxis is poorly understood. To explore the biochemical events underlying chemotaxis, we isolated C. elegans mutants that displayed abnormal chemotactic responses to cAMP, a strong attractant for C. elegans. Based on their responses to other chemoattractants, the mutant animals could be classified into five groups: (1) animals with defective chemotaxis to cAMP only; (2) animals with defective chemotaxis to both cAMP and cGMP; (3) animals with defective chemotaxis to water‐soluble attractants; (4) animals with defective chemotaxis to both water‐soluble and volatile attractants; and (5) animals with enhanced chemotactic responses. We expect that analyses of these mutants will help understand the molecular mechanisms underlying chemotaxis in C. elegans.
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Chemotaxis assay
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Many new chemokines have been described in recent years, resulting in a new classification of these chemoattractant proteins. The characterization of the biological functions of most chemokines relates to their ability to induce chemotaxis in circulating inflammatory cells. However, it is now clear that chemokines have a much wider biological role, including angiogenesis, carcinogenesis and involvement in the pathogenesis of HIV infection. Our understanding of the role of chemokines in the pathogenesis of disorders of the lungs and brain outstrips that with regard to disorders of the liver. An increased understanding of the role of chemokines in the pathogenesis of liver disease may lead to the development of novel therapies for hepatic disease.
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Objective To investigate the method of chemotactic migration of bronchial epithelial cells( BECs). Methods Determine chemotaxis of BECs by using insulin as chemotactic factor in different concentration and cultured time. Result A concentration dependent response between insulin and the chemotaxis of BECs was found. The optimal chemotactic migration of BECs were cultured within 6 h. Conclustion The method for determing chemotaxis of BECs was stable and dependable.
Chemotaxis assay
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Many new chemokines have been described in recent years, resulting in a new classification of these chemoattractant proteins. The characterization of the biological functions of most chemokines relates to their ability to induce chemotaxis in circulating inflammatory cells. However, it is now clear that chemokines have a much wider biological role, including angiogenesis, carcinogenesis and involvement in the pathogenesis of HIV infection. Our understanding of the role of chemokines in the pathogenesis of disorders of the lungs and brain outstrips that with regard to disorders of the liver. An increased understanding of the role of chemokines in the pathogenesis of liver disease may lead to the development of novel therapies for hepatic disease.
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The present study was designed to discriminate and analyze the presence of direct PMN chemotaxis and leucocyte‐induced PMN chemotaxis in filter assay systems of PMN chemotaxis, namely the Wilkinson chamber and the Boyden chamber, which yield a more quantified information on leucocyte chemotaxis than filming of vital cells. The PMN chemotaxis was reduced by approximately 30–35 μm after incubation with vinblastine, 0.01, 0.10 and 1.00 μg/ml respectively, as measured by the leading front method in the Wilkinson chamber. This figure was thought to represent the contribution of the leucocyte‐induced antitubulin‐sensitive PMN chemotaxis to the casein‐induced PMN chemotaxis under the experimental conditions prevailing. The remaining 60 μm antitubulin‐insensitive PMN migration into the filter probably represented a combination of direct PMN chemotaxis and stimulated PMN random motility. Since the above‐mentioned vinblastine inhibition of PMN chemotaxis was recorded in the absence of serum, complement factors included, the vinblastine‐inhibited PMN chemotaxis was thought to be due to the release of a leucocyte‐derived cytotaxin. The significance of incubation time and chemotactic parameters was further analyzed in the presence of serum in Boyden chambers, in the intercompartmental filters by means of PMN distribution curves and on the bottom filter by cell numbers. The antitubulin inhibition of PMN chemotaxis was evident in the intercompartmental filter during the initial period of incubation and later by cell counts on the bottom filter. These observations suggested that the antitubulin inhibition of PMN chemotaxis was due to antitubulin inhibition of the direction‐finding in a minor proportion of fast‐moving PMNs.
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