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)

The inflammatory response to tissue injury is a multi-faceted process. During this process, neutrophils migrate in the extravascular spaces, directed to the site of injury by chemical gradients generated by chemotactic molecules. S100A8, a protein associated with a wide variety of inflammatory conditions, is heavily over-expressed in association with inflammation. We hypothesized that human S100A8 possesses neutrophil-repelling properties that result in an anti-inflammatory effect in vivo. The chemotactic activity of S100A8 on neutrophils was tested in Transwell chemotaxis assays. Analysis of the data indicates that S100A8 causes a repulsion of peripheral neutrophils, an activity that S100A8 loses upon its oxidation. Using a mutant of S100A8 resistant to oxidation and consistent with the in vitro findings, we demonstrated that S100A8 causes a strong anti-inflammatory effect in the rat air-pouch model of inflammation in vivo. These data highlight a naturally occurring novel anti-inflammatory pathway and provide potential molecular targets for the development of novel anti-inflammatory therapeutics. Abbrevations: ethylene diamine tetraacetic acid (EDTA); limulus amoebocyte lysate assay (LAL); pertussis toxin (PTX); forward scatter (FSC); Interleukin-8 (IL-8); formyl-Met-Leu-Phe (fMLP); monocyte chemotactic protein 1 (MCP1).
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PMID:S100A8 triggers oxidation-sensitive repulsion of neutrophils. 1693 66

Enteral arginine supplementation in the critically ill has become a matter of controversy. In this study, we investigated effects of the addition of 0.4 and 1.2 mmol/L arginine in a coculture model on markers of inflammation, enterocyte layer integrity, and amino acid transport. In this model, a monolayer of intestinal epithelial cells (Caco-2) separated compartments with nonpathogenic Escherichia coli and mononuclear leukocytes. Activation of enterocytes and leukocytes was assessed by the measurement of nitric oxide, TNF-alpha, IL-6, IL-8, IL-10, and IFN-gamma. Further outcomes were the transepithelial flux of 22 amino acids, their catabolism, and the integrity of the enterocyte layer assessed as permeability of fluorescein dextran (M(r) 4400). Bacterial stimulation of intestinal epithelial cells enhanced the basolateral concentration of nitric oxide and all cytokines measured. Supplementation with arginine did not affect epithelial integrity, production of any of the cytokines investigated, or the amount of nitric oxide. The amino acid used primarily by nonstimulated intestinal epithelial cells cocultured with leukocytes was glutamine. Activation of IEC with bacteria significantly enhanced the catabolism of serine, asparagine, and lysine, and reduced glutamine catabolism. Addition of arginine increased ornithine formation and moderately reduced transepithelial transport of methionine and other amino acids. Hence, arginine supplementation does not interfere with inflammation-associated cross-talk between human enterocytes and leukocytes. Because it also does not seem to affect the integrity of enterocyte layers, a detrimental role of arginine during septic-like conditions seems unlikely.
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PMID:Arginine does not exacerbate markers of inflammation in cocultures of human enterocytes and leukocytes. 1718 9

The response of fibroblast-like synoviocytes (FLS) to inflammatory stimuli was compared to their, respectively, derived dermal fibroblasts (DF) to determine whether regulatory controls exist within FLS to insure normal joint homeostasis. We further analyzed whether the loss of the normal regulatory controls present within the FLS could predispose to the development of non-rheumatic joint disease (non-RA). Primary fibroblast cell lines were generated from synovial and skin tissue from ten rheumatoid arthritis (RA) and ten non-RA patients. Cell lines were pulse labeled with [(35)S]-methionine and stimulated with TNFalpha or IL-1beta. Protein synthesis of IL-1beta, IL-6 and IL-8 was quantitated following immunoprecipitation. Gene expression was determined by Northern blot analysis. We noted, IL-1beta was minimally detected in FLS under nonstimulated conditions. In response to stimulation with IL-1beta or TNFalpha, production of IL-1beta was found to be 3.5 and 5-fold lower in FLS, respectively, when compared to DF from the same individual. In contrast, the production of IL-6 and IL-8 in FLS upon stimulation was 3-fold and 1.6-fold higher, respectively, than in DF. Furthermore, induced IL-1beta production in FLS, normalized relative to their, respectively, stimulated DF, was 2.5 times higher in non-RA versus RA-derived cells (p=0.032), an effect noted even after several passages of growth. Our data suggest that inductive expression of IL-1beta in FLS is under specific inhibitory control. Increased production of IL-1beta in FLS of susceptible individuals may lead to a higher risk of developing severe joint damage even in the absence of systemic inflammation.
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PMID:Decreased induction of IL-1beta in fibroblast-like synoviocytes: a possible regulatory mechanism maintaining joint homeostasis. 1735 49

Chemokines and their receptors are key factors in the onset and progression of AIDS. Among them, accumulating evidence strongly indicates the involvement of IL-8 and its receptors, CXCR1 and CXCR2, in AIDS-related conditions. Through extensive investigation of genetic variations of the human CXCR1-CXCR2 locus, we identified a haplotype of the CXCR1 gene (CXCR1-Ha) carrying two nonsynonymous single nucleotide polymorphisms, CXCR1_300 (Met to Arg) in the N terminus extracellular domain and CXCR1_142 (Arg to Cys) in the C terminus intracellular domain. Transfection experiments with CXCR1 cDNAs corresponding to the CXCR1-Ha and the alternative CXCR1-HA haplotype showed reduced expression of CD4 and CXCR4 in CXCR1-Ha cells in human osteosarcoma cells as well as in Jurkat and CEM human T lymphocytes. Furthermore, the efficiency of X4-tropic HIV-1(NL4-3) infection was significantly lower in CXCR1-Ha cells than in CXCR1-HA cells. The results were further confirmed by a series of experiments using six HIV-1 clinical isolates from AIDS patients. A genetic association study was performed by using an HIV-1(+) patient cohort consisting of two subpopulations of AIDS with extreme phenotypes of rapid and slow progression of the disease. The frequency of the CXCR1-Ha allele is markedly less frequent in patients with rapid disease onset than those with slow progression (P = 0.0003). These results provide strong evidence of a protective role of the CXCR1-Ha allele on disease progression in AIDS, probably acting through modulation of CD4 and CXCR4 expression.
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PMID:A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients. 1736 Jun 50

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

gp130-linked cytokines such as interleukin-6 (IL-6) stimulate the formation of tyrosine-phosphorylated signal transducer and activator of transcription 3 (P-STAT3), which activates many genes, including the STAT3 gene itself. The resulting increase in the concentration of unphosphorylated STAT3 (U-STAT3) drives a second wave of expression of genes such as RANTES, IL6, IL8, MET, and MRAS that do not respond directly to P-STAT3. Thus, U-STAT3 sustains cytokine-dependent signaling at late times through a mechanism completely distinct from that used by P-STAT3. Many U-STAT3-responsive genes have kappaB elements that are activated by a novel transcription factor complex formed when U-STAT3 binds to unphosphorylated NFkappaB (U-NFkappaB), in competition with IkappaB. The U-STAT3/U-NFkappaB complex accumulates in the nucleus with help from the nuclear localization signal of STAT3, activating a subset of kappaB-dependent genes. Additional genes respond to U-STAT3 through an NFkappaB-independent mechanism. The role of signal-dependent increases in U-STAT3 expression in regulating gene expression is likely to be important in physiological responses to gp130-linked cytokines and growth factors that activate STAT3, and in cancers that have constitutively active P-STAT3.
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PMID:Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. 1751 Feb 82

The amine-carboxyboranes and related derivatives have been shown to be potent anti-inflammatory and anti-osteoporosis agents. Their action in part appears to be mediated by the modulation of cytokines, e.g. TNFalpha or IL-1. Previous studies have demonstrated that LPS induced macrophages release of TNFalpha maximally at 60 to 90 min. and IL-1 from 5 to 8 hr. The amine-carboxyboranes reduced significantly the release of these cytokines but also blocked TNFalpha high affinity binding to UMR-106 receptor at 90 min. at 10 muM, and IL-1 high affinity binding at 5 hr. at 12.5 muM. In addition, the agents suppressed IL-8 binding to CHO K1 high affinity receptor at 24 hr. at 50 muM and IL-2 binding to HuT-8 receptors at 25 muM at 90 min. and 5 hr. Correlation of metabolic events associated with osteoporosis showed that at 90 min., when TNFalpha receptor binding was reduced by the agents, calcium uptake into UMR-106 cells was reduced at 10 muM as well as the acid and alkaline phosphatases, and the prostaglandin cyclo-oxygenase activities and adhesion of leukocytes and macrophages to UMR-106 cell monolayers. At 5hr. when the agents reduced IL-1 binding to UMR-106 receptors, calcitonin and 1,25-dihydrovitamin D(3) binding was reduced by the agents as was acid and alkaline phosphatase, and 5'-lipoxygenase activities and white blood cell adhesion. At this time calcium uptake and proline incorporation was increased significantly by the agents. At later times e.g. 18-48 hr. calcium uptake was still increased, and NAG activity was inhibited in the presence of the agents. These effects may be related more to the inhibition of other cytokine receptor binding, e.g. IL-8. Thus, many of the observed metabolic effects of amine-carboxyboranes as antiosteoporosis agents can be correlated with their inhibition of cytokine high affinity binding to target cell receptors.
Met Based Drugs 1996
PMID:The Effects of Amine-Carboxyborane Related Derivatives on UMR-106 Bone Metabolism. 1847 91

Monocytes/macrophages recruited into the arterial wall during atherogenesis are crucial in the initiation and progression of atherosclerosis and play a fundamental role in the destabilization process that is the main causal event of acute coronary syndromes. In the present study, we investigated the effect of the mammalian target of rapamycin inhibitor everolimus on macrophage accumulation within carotid lesions elicited by perivascular collar placement in cholesterol-fed rabbits. Everolimus (1.5 mg/kg given 1 day before collaring followed by 1 mg/kg/day for 14 days, administered by oral gavage) markedly decreased lesion macrophage content as compared with vehicle control (-65%; p < 0.01). This effect was associated with a reduction in intimal thickening and occurred in the absence of changes in plasma cholesterol concentrations. To gain insights on the potential mechanism(s) underlying this effect, we investigated the influence of everolimus on chemoattractant-induced migration of human monocytes in vitro. Pretreatment with therapeutic concentrations of everolimus (10 nM) significantly lowered monocyte chemotaxis in response to various chemotactic factors (i.e., monocyte chemoattractant protein-1/CCL2, fractalkine/CX3CL1, interleukin-8/CXCL8, complement fragment 5a, or N-formyl-Met-Leu-Phe) without inducing monocyte cell death. These results suggest that everolimus may favorably influence the atherosclerotic process by affecting the recruitment of monocytes into early lesions.
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PMID:Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits. 1902 42

The current gold standard for imaging infection is radiolabeled white blood cells. For reasons of safety, simplicity and cost, it would be desirable to have a receptor-specific ligand that could be used for imaging infection and that would allow a differential diagnosis between sterile and septic inflammatory processes. Ligands tested for this purpose include labeled peptides ((99m)Tc-labeled f-Met-Leu-Phe, (123)I-IL-1ra, (99m)Tc-IL-8, (99m)Tc-P483H, (99m)Tc-P1827DS, (99m)Tc-C5a-des-Arg, (99m)Tc-RP517, (11)In-DPC11870-11), human polyclonal antibodies, monoclonal antibodies, antibody fragments, antimicrobial agents (ciprofloxacin, sparfloxacin, ceftizoxime, isoniazid, ethambutol, fluconazole, all labeled with (99m)Tc), antimicrobial peptides and bacteriophages. Radiolabeled antibodies represent a valid alternative to labeled white blood cells under specific conditions and indications. Radiolabeled antibiotics and antimicrobial peptides are promising candidates for an infection-specific radiopharmaceutical. However, at present we still need to investigate many basic aspects to better understand the mechanisms of binding and accumulation of this class of radiopharmaceuticals to bacteria.
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PMID:Receptor binding ligands to image infection. 1907 10

Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.
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PMID:Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. 1912 57


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