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)

We have previously demonstrated that a basic amino acid residue of interleukin (IL)-8, namely Arg-6, is critical for the binding of IL-8 to its receptor. We reasoned that this residue is likely to be poised to directly interact with a counterpart acidic residue on the receptor. To identify this key residue, we systematically mutated to Ala all acidic residues present on the ligand accessible surface of IL-8 receptor type A. Using this strategy, we demonstrate that two residues which are present in extracellular loop 3 of the receptor, namely Glu-275 and Arg-280, are critical for ligand binding. In addition, we show that although Asp-11 is critical for ligand binding, a conservative mutation of Asp-11 to Glu or a substitution of Asp-11 with Lys (the residue found at position 11 in IL-8 receptor type B) does not affect the Kd of the receptor/ligand interaction. These data suggest that Lys-11 recruits a new and favorable interaction with IL-8 (analogous to that of IL-8 receptor type B with IL-8) or that the cavity created by mutating Asp-11 to Ala is particularly deleterious. Finally, we discuss fluorescence-activated cell sorter staining data which support the hypothesis that the N-terminal region and the extracellular loop 3 of the receptor may lie in close proximity of one another and constitute a major binding domain for IL-8.
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PMID:Partial functional mapping of the human interleukin-8 type A receptor. Identification of a major ligand binding domain. 810 45

The cutaneous lymphocyte-associated antigen (CLA) is a carbohydrate epitope present on memory/effector T cells that infiltrate inflamed skin. E-selectin is the ligand for CLA and is induced under inflammation on endothelial cells. CLA was originally postulated as a phenotype marker for skin-associated T cells. We studied the specific in vitro response to skin-associated allergens of CLA+ and CLA-CD45RO+ T cells in atopic dermatitis (AD) and contact dermatitis (CD), which represent two well-characterized T cell-mediated cutaneous allergic inflammations. Whereas CLA+ T cells from AD patients preferentially responded to house dust mite (HDM) and CLA+ T cells from nickel CD patients showed an increased response to nickel, CLA-T cells showed very little response in both cases. In contrast, tetanus toxoid, a systemically acting antigen, induced a proliferative response in both CLA+ and CLA- cells. Interestingly the response to HDM in patients with asthma +/- AD was preferentially found in the CLA- subset indicating the involvement of different homing receptors for mucosal tissues. Moreover, CLA+ T cells showed enhanced migration through activated human umbilical vein endothelial cell monolayers compared to CLA- T cells. The CLA binding to E-selectin is initially responsible for the extravasation that also involves VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions. We have recently identified IL-8 as an endothelial cell-derived chemokine and the IL-8 receptor type B which control CLA+ T cell migration. Such a CLA-mediated migration would localize memory/effector T cells that respond to antigens and reach the body through inflamed skin. Our data support the existence of a regionalization of the immune system and in particular of the skin immune system. It may allow an efficient distribution of the immune defense to different sites of the body.
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PMID:Skin-homing T cells in human cutaneous allergic inflammation. 872 46

Many chemoattractants cause chemotaxis of leukocytes by stimulating a structurally distinct class of G protein-coupled receptors. To identify receptor functions required for chemotaxis, we studied chemotaxis in HEK293 cells transfected with receptors for nonchemokine ligands or for interleukin 8 (IL-8), a classical chemokine. In gradients of the appropriate agonist, three nonchemokine Gi-coupled receptors (the D2 dopamine receptor and opioid mu and delta receptors) mediated chemotaxis; the beta2-adrenoreceptor and the M3-muscarinic receptor, which couple respectively to Gs and Gq, did not mediate chemotaxis. A mutation deleting 31 C-terminal amino acids from the IL-8 receptor type B quantitatively impaired chemotaxis and agonist-induced receptor internalization, but not inhibition of adenylyl cyclase or stimulation of mitogen-activated protein kinase. To probe the possible relation between receptor internalization and chemotaxis, we used two agonists of the mu-opioid receptor. Morphine and etorphine elicited quantitatively similar chemotaxis, but only etorphine induced receptor internalization. Overexpression of two betagamma sequestering proteins (betaARK-ct and alphat) prevented IL-8 receptor type B-mediated chemotaxis but did not affect inhibition of adenylyl cyclase by IL-8. We conclude that: (i) Nonchemokine Gi-coupled receptors can mediate chemotaxis. (ii) Gi activation is necessary but probably not sufficient for chemotaxis. (iii) Chemotaxis does not require receptor internalization. (iv) Chemotaxis requires the release of free betagamma subunits.
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PMID:Receptors induce chemotaxis by releasing the betagamma subunit of Gi, not by activating Gq or Gs. 940 40

We give here evidence that Purkinje neurons (PNs) of mouse cerebellar slices studied with patch clamp technique combined with laser confocal microscopy, respond to human IL-8 and GROalpha by (i) a cytosolic Ca2+ transient compatible with inositol (1,4,5) trisphosphate (InsP3) formation; (ii) an enhancement of the neurotransmitter release; and (iii) an impairment of the long-term depression of synaptic strength (LTD). It was also found the expression of IL-8 receptor type 2 in PN and granule cells by immunofluorescence, immunoblotting and RT-PCR analysis. Considered together these findings suggest that IL-8 and GROalpha may play a neuromodulatory role on mouse cerebellum.
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PMID:CXC chemokines interleukin-8 (IL-8) and growth-related gene product alpha (GROalpha) modulate Purkinje neuron activity in mouse cerebellum. 991 87

Little is known about the mechanisms controlling the expression of key proteins that regulate excitability and contractility in the human myometrium at term. However, evidence is accumulating to suggest that the cytokine transforming growth factor (TGF)beta may play a central role. TGFbeta1 and TGFbeta receptors are present in the myometrial cells, indicative of an autocrine signaling system. Furthermore, the levels of TGFbeta1 and the expression of its receptors increase in the myometrium at term suggesting that they are, in turn, regulated and form part of a physiological cascade of events involving a number of autocrine signaling associated proteins. The present experiments were done to identify factors that regulate the expression of TGFbeta1 and TGFbeta receptors and may form other elements of this cascade. Because IL-1 and IL-8 are found in the myometrium at term and have been implicated in the etiology in premature labor we focus on this cytokines. Receptors for IL-1 and IL-8 were detected in the myometrial cells. Using Western blot analysis, the levels of expression were found to vary. The expression of IL-1 receptor type I was highest in the nonpregnant tissue with lower levels in nonlaboring myometrium with a further reduction in the spontaneously laboring tissue. In contrast, the expression of IL-8 receptor type B was highest in the pregnant nonlaboring tissue with a lower level in the spontaneously laboring tissue. Using an in vitro model, TGFbeta1 and TGFbeta receptor expression was up-regulated by IL-8, IL-1, and TGFbeta1 itself. However, IL-8 receptor expression was decreased by IL-8 and TGFbeta1. This suggests that in a cascade IL-8 would feed forward to promote the TGFbeta system, whereas TGFbeta1 feeds back to inhibit responsiveness to IL-8. Estrogen and progesterone increased the release of TGFbeta1. However, at high concentrations, estrogen and progesterone (100 nM 17beta-estradiol or 200 nM progesterone) decreased the level of TGFbeta receptor expression. Thus, the progressive rise of steroid levels in vivo might account for the observed changes in TGFbeta1 and TGFbeta receptor expression in vivo. Taken together, these observations support the idea that there is a cascade of autocrine signals that may play a major role in the physiological processes preparing the myometrium for parturition at term.
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PMID:Complex interactions between sex steroids and cytokines in the human pregnant myometrium: evidence for an autocrine signaling system at term. 1034 39

We have previously shown that members of the ELR(+) CXC chemokine family, including IL-8; growth-related oncogenes alpha, beta, and gamma; granulocyte chemotactic protein 2; and epithelial neutrophil-activating protein-78, can mediate angiogenesis in the absence of preceding inflammation. To date, the receptor on endothelial cells responsible for chemotaxis and neovascularization mediated by these ELR(+) CXC chemokines has not been determined. Because all ELR(+) CXC chemokines bind to CXC chemokine receptor 2 (CXCR2), we hypothesized that CXCR2 is the putative receptor for ELR(+) CXC chemokine-mediated angiogenesis. To test this postulate, we first determined whether cultured human microvascular endothelial cells expressed CXCR2. CXCR2 was detected in human microvascular endothelial cells at the protein level by both Western blot analysis and immunohistochemistry using polyclonal Abs specific for human CXCR2. To determine whether CXCR2 played a functional role in angiogenesis, we determined whether this receptor was involved in endothelial cell chemotaxis. We found that microvascular endothelial cell chemotaxis in response to ELR(+) CXC chemokines was inhibited by anti-CXCR2 Abs. In addition, endothelial cell chemotaxis in response to ELR(+) CXC chemokines was sensitive to pertussis toxin, suggesting a role for G protein-linked receptor mechanisms in this biological response. The importance of CXCR2 in mediating ELR(+) CXC chemokine-induced angiogenesis in vivo was also demonstrated by the lack of angiogenic activity induced by ELR(+) CXC chemokines in the presence of neutralizing Abs to CXCR2 in the rat corneal micropocket assay, or in the corneas of CXCR2(-/-) mice. We thus conclude that CXCR2 is the receptor responsible for ELR(+) CXC chemokine-mediated angiogenesis.
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PMID:The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. 1104 61

The development of adhesions in the peritoneal and pelvic cavities, which commonly form after surgery or infection, cause significant morbidity and mortality. However, the pathogenesis of adhesion formation is still poorly understood. Because T cells are important in orchestrating fibrinogenic tissue disorders, we hypothesized that they play a critical role in the pathogenesis of peritoneal adhesion formation. Using a cecal abrasion surgical model in rodents, T cell depletion and adoptive transfer experiments demonstrated that this host response is dependent on CD4+ alphabeta T cells. These cells were also critical to adhesion formation associated with experimental intraabdominal sepsis. T cell transfer studies with mice deficient in signal transducer and activator of transcription (Stat)4 and Stat6 revealed that adhesion formation was dependent on a T helper 1 response. Activated T cells homed to the peritoneal cavity 6 hours after cecal abrasion surgery and predominated at this site during adhesiogenesis. Increased levels of the T cell-derived proinflammatory cytokine interleukin (IL)-17 and of neutrophil chemoattractant CXC chemokines macrophage inflammatory protein-2/CXCL8 and cytokine-induced neutrophil chemoattractant/CXCL1 were associated with adhesion formation. The production of these chemokines was dependent on T cells. Furthermore, the administration of neutralizing antibodies specific for IL-17 or the receptor that binds these CXC chemokines, CXC chemokine receptor 2, significantly reduced the degree of adhesion formation. These results demonstrate for the first time that the immunopathogenesis of adhesion formation is under the control of T cells and that T cell-derived cytokines and chemokines play important roles in the development of this deleterious host response.
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PMID:CD4+ T cells regulate surgical and postinfectious adhesion formation. 1204 45

Helicobacter pylori (HP) infection elevates the risk of gastric diseases including peptic ulcer and gastric cancer. The infection induces inflammatory cytokines, which could work both for and against lifetime infection in the human stomach. Genetic polymorphisms of the cytokines and other related ligands, receptors, and enzymes may influence persistent HP infection. This paper summarizes studies done on the associations between anti-HP antibody seropositivity and polymorphism genotypes. To date, the associations with the polymorphisms of fucosyl transferase 2 (FUT2 or secretor gene), FUT3 (Lewis gene), interleukin 1A (IL-1A), IL-1B, IL-1RN, IL-8, IL-10, myeloperoxidase (MPO), and tumor necrosis factor A (TNF-A) and TNF-B have been reported. Polymorphisms of other related genes, CD14, CXC chemokine receptor 2 (CXCR2), IL-1RI, nuclear factor KB2 (NF-KB2), and Toll-like receptor 4 (TLR4), have the potential to influence persistent infection. Unpublished results from our datasets are reported here for all these polymorphisms except TLR4. Gene-environment interactions between these genotypes and smoking are reviewed. An effect on OR due to the involvement of unexposed subjects is demonstrated to elucidate a disadvantage in the studies done in areas where the majority of the population is not exposed to HP.
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PMID:Persistent Helicobacter pylori infection and genetic polymorphisms of the host. 1472 87

While the mechanisms underlying the marked sexual dimorphism in inflammatory diseases are not well understood, the sexually dimorphic sympathoadrenal axis profoundly affects the inflammatory response. We tested whether adrenergic receptor-mediated activation of human neutrophil function is sexually dimorphic, since neutrophils provide the first line of defense in the inflammatory response. There was a marked sexual dimorphism in beta(2)-adrenergic receptor binding, using the specific beta(2)-adrenergic receptor ligand, [(3)H]-dihydroalprenolol, with almost three times more binding sites on neutrophils from females (20,878 +/- 2470) compared to males (7331 +/- 3179). There was also a marked sexual dimorphism in the effects of isoprenaline, a beta-adrenergic receptor agonist, which increased nondirected locomotion (chemokinesis) in neutrophils obtained from females, while having no effect on neutrophils from males. Isoprenaline stimulated the release of a chemotactic factor from neutrophils obtained from females, but not from males. This chemotactic factor acts on the G protein-coupled CXC chemokine receptor 2 (CXCR2) chemokine receptor, since an anti-CXCR2 antibody and the selective nonpeptide CXCR2 antagonist SB225002, inhibited chemotaxis produced by this factor. While interleukin- (IL-) 8 is a principal CXCR2 ligand, isoprenaline did not produce an increase in IL-8 release from neutrophils. IL-8-induced chemotaxis was inhibited in a sexually dimorphic manner by isoprenaline, which also stimulated release of a mediator from neutrophils that induced chemotaxis, that was inhibited by anti-CXCR2 antibodies. These findings indicate an important role for adrenergic receptors in the modulation of neutrophil trafficking, which could contribute to sex-differences in the inflammatory response.
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PMID:Beta 2-adrenergic receptor regulation of human neutrophil function is sexually dimorphic. 1547 26

The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.
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PMID:2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors. 1597 85


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