Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CXCL8 (interleukin-8) interacts with two receptors, CXCR1 and CXCR2, to activate leukocytes. Upon activation, CXCR2 internalizes very rapidly relative to CXCR1 ( approximately 90% versus approximately 10% after 5 min). The C termini of the receptors have been shown to be necessary for internalization but are not sufficient to explain the distinct kinetics of down-regulation. To determine the structural determinant(s) that modulate receptor internalization, various chimeric and point mutant receptors were generated by progressively exchanging specific domains or amino acids between CXCR1 and CXCR2. The receptors were stably expressed in rat basophilic leukemia 2H3 cells and characterized for receptor binding, intracellular Ca(2+) mobilization, phosphoinositide hydrolysis, phosphorylation, internalization, and MAPK activation. The data herein indicate that the second extracellular loop (2ECL) of the receptors is critical for the distinct rate of internalization. Replacing the 2ECL of CXCR2 with that of CXCR1 (B(2ECL)A) or Asp(199) with its CXCR1 valine counterpart (B(D199V)A) delayed CXCR2 internalization similarly to CXCR1. Replacing Asp(199) with Asn (B(D199N)) restored CXCR2 rapid internalization. Structure modeling of the 2ECL of the receptors also suggested that Asp(199) plays a critical role in stabilizing and modulating CXCR2 rapid internalization relative to CXCR1. B(D199N) internalized rapidly but migrated as a single phosphorylated form like CXCR1 ( approximately 75 kDa), whereas B(2ECL)A and B(D199V)A showed slow and fast migrating forms like CXCR2 ( approximately 45 and approximately 65 kDa, respectively) but internalized like CXCR1. These data further undermine the role of receptor oligomerization in CXCL8 receptor internalization. Like CXCR1, B(D199V)A also induced sustained ERK activation and cross-desensitized Ca(2+) mobilization to CCR5 relative to B(D199N) and CXCR2. Altogether, the data suggest that the 2ECL of the CXCL8 receptors is important in modulating their distinct rate of down-regulation and thereby signal length and post-internalization activities.
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PMID:CXCR1 and CXCR2 activation and regulation. Role of aspartate 199 of the second extracellular loop of CXCR2 in CXCL8-mediated rapid receptor internalization. 1720 68

Neuro-immune interactions are increasingly relevant to human health and disease. The neuropeptide Substance P also has antibacterial activity and bears similarities to the innate immune antibacterial defensins. This suggests possible co-regulation of neuropeptide and innate immune mediators. In this study, non-bronchoscopic bronchoalveolar lavage (BAL) was performed on 69 children. BAL was examined for cellular profile, microbiology (bacteria, virus) and gene expression for TLRs 2, 3, 4; chemokine receptors (CCR3, CCR5, CXCR1); neurotrophins and neurokinin genes (TAC1, TAC3, CGRP, NGF). In children with bacterial colonization (n=10) there was an airway inflammatory response with increased BAL neutrophils, IL-8 protein, and CXCR1 expression. Substance P (TAC1) and TLR4 RNA expression were reduced in children with bacterial colonization. TLR3 mRNA was increased in 7.2% (n=5) children with rhinovirus, and there was a non-significant trend to increased TLR2. There is evidence for co-regulation of neurokinin (TAC1) and TLR4 gene expression in airway cells from children with airway bacterial colonization and their reduced expression may be associated with an impaired bacterial clearance.
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PMID:Reduced toll-like receptor 4 and substance P gene expression is associated with airway bacterial colonization in children. 1735 43

Attraction of mononuclear cells to sites of inflammation requires a close interplay of the inflammatory signal presented via chemokines and specific receptors on effector cells. First studies on acute renal transplant rejection demonstrated the involvement of CC-chemokines, such as RANTES, MIP-1alpha, MIP-1beta and MCP-1, as well as CXC-chemokines such as IL-8 and IP-10, correlating with expression of the corresponding chemokine receptors, CCR1, CCR5 and CCR2 as well as CXCR3. Since then, the pathophysiologic relevance has been extended to chronic allograft nephropathy and transplant glomerulopathy. Chemokine expression can be triggered by different stimuli, e.g. brain death, ischemia, HLA-mismatch and infection. Furthermore, anti-inflammatory chemokines have been identified. Chemokine receptor 7, e.g. enhances homing of lymphocytes to lymphatic tissues and the Duffy antigen receptor, DARC, a non-specific receptor that binds and inactivates different chemokines. While measurement of chemokine expression in clinical transplantation may facilitate the differential diagnosis of allograft dysfunction, knowledge of the chemokine network has also widened the understanding of transplant rejection and opened novel therapeutic approaches. Observations from humans with mutations of the chemokine network as well as transplantation of animals with targeted deletions in this system suggest that manipulations of chemokine signalling may improve the success rates of transplantation. Blocking chemokines unselectively with Met-RANTES or specifically with small molecule inhibitors of various chemokine receptors has lead to improved outcome in animal models. Currently, first human trials are under way to investigate drugs that stimulate lymphocyte homing. Inhibitors of CCR1 and CCR5 are being tested for other human diseases and may eventually be available in transplantation. Nonetheless, chemokine blockade my rather serve as an adjunct in the management of transplant recipients than a new "magic bullet".
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PMID:Chemokines and chemokine receptors in renal transplantation--from bench to bedside. 1744 76

Rheumatoid arthritis (RA) is characterized by the recruitment of leukocytes and the accumulation of inflammatory mediators within the synovial compartment. Release of the chemokine CCL18 has been widely attributed to antigen-presenting cells, including macrophages and dendritic cells. This study investigates the production of CCL18 in polymorphonuclear neutrophils (PMN), the predominant cell type recruited into synovial fluid (SF). Microarray analysis, semiquantitative and quantitative reverse transcriptase polymerase chain reaction identified SF PMN from patients with RA as a novel source for CCL18 in diseased joints. Highly upregulated expression of other chemokine genes was observed for CCL3, CXCL8 and CXCL10, whereas CCL21 was downregulated. The chemokine receptor genes were differentially expressed, with upregulation of CXCR4, CCRL2 and CCR5 and downregulation of CXCR1 and CXCR2. In cell culture experiments, expression of CCL18 mRNA in blood PMN was induced by tumor necrosis factor alpha, whereas synthesis of CCL18 protein required additional stimulation with a combination of IL-10 and vitamin D3. In comparison, recruited SF PMN from patients with RA were sensitized for CCL18 production, because IL-10 alone was sufficient to induce CCL18 release. These results suggest a release of the T cell-attracting CCL18 by PMN when recruited to diseased joints. However, its production is tightly regulated at the levels of mRNA expression and protein synthesis.
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PMID:Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. 1787 2

Strong evidence suggests that neutrophils may play an active role in acute and chronic inflammatory disorders, such as rheumatoid arthritis and atherosclerosis. Given the role of pro-inflammatory cytokine TNF-alpha in these inflammatory processes, we planned the present study to investigate the effect of short term incubation with TNF-alpha on neutrophil migration to CCL3, a chemokine produced in inflammatory sites and normally devoid of neutrophil chemotactic properties. We found that TNF-alpha primed neutrophils for migration to CCL3 via CCR5. TNF-alpha-induced migration was a consequence of the TNF-alpha-induced up-regulation of integrin CD11b/CD18 (Mac-1) on neutrophil surface. Furthermore, TNF-alpha activity was found to be strictly dependent on the activation of ERK 1/2 p44, cooperating with the intracellular pathways involving Src kinases, PI3K/Akt, p38 MAPK, well known as activated in response to classical chemoattractants (CXCL8) or priming agents (GM-CSF). On the contrary, the effect of TNF-alpha on neutrophil migration to CCL3 was not dependent on JNK 1/2. In conclusion, the present report shows that TNF-alpha unveils a previously unknown capacity of neutrophils to migrate to CCL3 through the intervention of Mac-1. TNF-alpha regulates Mac-1 up-regulation through signalling pathways, involving various kinases, but not JNK 1/2. Although highly speculative, ERK 1/2 p44 may represent a selective target for the pharmacologic manipulation of neutrophil-mediated adverse activities in TNF-alpha-mediated inflammatory states.
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PMID:Tumor necrosis factor-alpha (TNF-alpha) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1alpha) on human neutrophils through defined signalling pathways. 1816 90

The physiological relevance of naturally occurring IgM-ALA remains to be elucidated. These autoantibodies are present from birth and increase in diverse inflammatory states that are both infectious and noninfectious. Clinical observations showing significantly less acute allograft rejections in recipients having high IgM-ALA levels, led us to investigate whether IgM-ALA could have a functional role in attenuating T cell mediated inflammatory responses. In pursuit of this hypothesis, we did studies using IgM purified from the serum of normal individuals, patients with end stage renal disease, and HIV-1 infection. All preparations of IgM immunoprecipitated certain receptors e.g., CD3, CD4, CCR5, and CXCR4 from whole cell lysates but failed to immunoprecipitate IL-2R and HLA Ags. In physiological doses IgM down-regulated CD4, CD2 and CD86 but not CD8 and CD28, inhibited T cell proliferation, decreased production of certain proinflammatory cytokines e.g., TNF-alpha, IL-13 and IL-2, but not IFN- gamma, IL-1beta, GM-CSF, IL-6 and IL-8 and inhibited leukocyte chemotaxis. These inhibitory effects were more pronounced when using IgM from patients with high levels of IgM-ALA and these inhibitory effects were significantly reduced after using IgM preabsorbed with leukocytes. IgM-ALA binding to leukocytes was found to be highly specific, as <10% of IgM secreting B cell clones had IgM-ALA specificity with some clones having specificity for either T cells or monocytes. These findings support the concept that IgM-ALA provides an innate mechanism to regulate T cell mediated inflammatory responses.
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PMID:Naturally occurring IgM anti-leukocyte autoantibodies (IgM-ALA) inhibit T cell activation and chemotaxis. 1820 75

Chemokines mediate their biological functions by transmigration of various immune cells to the site of infection. Tuberculous pleurisy provides an effective model to study the role of chemokines in the recruitment of immune cells to the pleura. Our aim was to understand the cumulative effect of chemokines (IP-10, MIG, IL-8, MCP-1, MIP-1alpha and RANTES) and its receptors (CXCR2, CXCR3, CCR1, CCR2, CCR5 and CCR7) in the recruitment of CD4(+) T cells obtained from blood (BL) and pleural fluid (PF) of tuberculous (TB) and non-tuberculous (NTB) patients. We observed significant increase in CD4(+) T cells in TB PF indicating lymphocytic rich effusion. All chemokines except RANTES were significantly high in PF compared to BL in TB group, whereas IL-8 and MCP-1 showed significant increase only in NTB PF. The significantly high levels of IFN-gamma and TauNuF-alpha in TB PF and their positive correlation with IP-10 and MIP-1alpha indicated their synergistic action to elicit a strong protective Th1 response. In spite of high levels of Th1 cytokines and chemokines in TB PF, significantly lower levels of RANTES indicated its limited role at the site. The CXC receptors in PF of both the groups and CC receptors except CCR5 in TB PF were significantly high compared to BL. Only CXCR2, CCR5 and CCR7 showed significant increase in TB compared to NTB. Thus a selective concentration of chemokines, cytokines and abundant expression of chemokine receptors confirm the accumulation of activated and memory T cells at the site of infection and help in polarizing Th1 immune response.
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PMID:Expression of CXC and CC type of chemokines and its receptors in tuberculous and non-tuberculous effusions. 1822 15

Dendritic cells (DCs) play a key role in the host immune response to infections. Mycobacterium tuberculosis (MTB) can inhibit the maturation of DCs and impair their ability to stimulate T cell proliferation. Here, we assessed in vitro migratory behavior of human monocyte-derived DCs (MoDC) when infected with various MTB strains (H37Rv and prevalent clinical strains S7 and S10 from South India). The migration of Rv and S7 infected MoDC towards secondary lymphoid chemokine (CCL21) was 50% lower after 1 day of infection compared to LPS stimulation. This reduced cell migration may be due to a block in the chemokine receptor switch from CCR5 to CCR7 expression on MoDC. Only clinical strain S10 infected MoDC showed an up-regulation of CCR7 and down-regulation of CCR5 expression, similar to LPS stimulated MoDC. While Rv and S7 infected MoDC did not display any alteration in expression of these receptors. Similarly, Rv and S7 infected MoDC did not induce IL-8, IP-10 and MCP-1 chemokine production. This reduction in chemokine levels was reflected in the reduced chemoattraction of CD4(+) T cells also. These findings suggest that there is variation in the stimulation of MoDC with different clinical strains of MTB and this variation may be dependent upon the virulence of the strain.
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PMID:Differential migration of human monocyte-derived dendritic cells after infection with prevalent clinical strains of Mycobacterium tuberculosis. 1865 4

Chemokines regulate leukocyte migration during physiological and pathological conditions. They exert their biological activity through interaction with 7-transmembrane spanning G protein-coupled receptors (GPCR) and are presented on glycosaminoglycans (GAG) linked to endothelial cell layers. Specific chemokines and chemokine receptors affect angiogenesis or are targets for viral mimicry, e.g. by human immunodeficiency virus (HIV). Several enzymes, in particular proteases, have been described to process chemokines at specific sites generating chemokine isoforms that were also identified from natural sources. For some chemokines, e.g. CXCL8 and CCL3L1, posttranslational modification results in enhanced biological activity. For CXCL7 and CCL14 truncation is even mandatory for receptor signaling and chemotactic properties. The activity of many other chemokines is down-regulated by processing and receptor antagonists are generated, e.g. for truncated CCL8 and CCL11. Moreover, some processed chemokines such as CCL5(3-68) show enhanced affinity for one receptor (CCR5) and reduced interaction with other receptors (CCR1 and CCR3) resulting in differential changes in leukocyte response. These posttranslational mechanisms, in addition to gene duplication, transcriptional and translational regulation of chemokine ligand and receptor expression, GAG binding properties, expression of "silent" receptors and synergistic interaction between chemokines, modulate chemokine activity in a complex manner. This report reviews current understanding on the regulation of the chemokine network through posttranslational modification and its consequences for leukocyte migration, angiogenesis and protection against viral infection.
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PMID:Regulation of chemokine activity by posttranslational modification. 1879 69

The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF-alpha-stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF-alpha for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF-alpha in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells.
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PMID:Differential regulation of chemokines by IL-17 in colonic epithelial cells. 1894 Dec 44


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