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 subcellular localization of Mac-1 was determined in resting and stimulated human neutrophils after disruption by nitrogen cavitation and fractionation on two-layer Percoll density gradients. Light membranes were further separated by high voltage free flow electrophoresis. Mac-1 was determined by an ELISA with monoclonal antibodies that were specific for the alpha-chain (CD11b). In unstimulated neutrophils, 75% of Mac-1 colocalized with specific granules including gelatinase granules, 20% with secretory vesicles and the rest with plasma membranes. Stimulation with nanomolar concentrations of FMLP resulted in the translocation of Mac-1 from secretory vesicles to the plasma membrane, and only minimal translocation from specific granules and gelatinase granules. Stimulation with PMA or Ionomycin resulted in full translocation of Mac-1 from secretory vesicles and gelatinase granules to the plasma membrane, and partial translocation of Mac-1 from specific granules. These findings were corroborated by flow cytometry, which demonstrated a 6-10-fold increase in the surface membrane content of Mac-1 in response to stimulation with FMLP, granulocyte-macrophage colony stimulating factor, IL-8, leukotriene B4, platelet-activating factor, TNF-alpha, and zymosan-activated serum, and a 25-fold increase in response to Ionomycin. Thus, secretory vesicles constitute the most important reservoir of Mac-1 that is incorporated into the plasma membrane during stimulation with inflammatory mediators.
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PMID:Subcellular localization and dynamics of Mac-1 (alpha m beta 2) in human neutrophils. 837 98

The human interleukin-3 receptor (IL-3R) is expressed on myeloid, lymphoid, and vascular endothelial cells, where it transduces IL-3-dependent signals leading to cell activation. Although IL-3R activation may play a role in hematopoiesis and immunity, its aberrant expression or excessive stimulation may contribute to pathologic conditions such as leukemia, lymphoma, and allergic reactions. We describe here the generation and characterization of a monoclonal antibody (MoAb), 7G3, which specifically binds to the IL-3R alpha-chain and completely abolishes its function. MoAb 7G3 immunoprecipitated and recognized in Western blots the IL-3R alpha-chain expressed by transfected cells and bound to primary cells expressing IL-3R alpha. MoAb 7G3 bound the IL-3R alpha-chain with a kd of 900 pmol/L and inhibited 125I-IL-3 binding to high- and low-affinity receptors in a dose-dependent manner. Conversely, IL-3 but not granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibited 125I-7G3 binding to high- and low-affinity IL-3Rs, indicating that MoAb 7G3 and IL-3 bind to common or adjacent sites. In keeping with the inhibition of IL-3 binding, MoAb 7G3 antagonized IL-3 biologic activities, namely stimulation of TF-1 cell proliferation, basophil histamine release, and IL-6 and IL-8 secretion from human endothelial cells. Two other anti-IL-3R alpha-chain MoAbs failed to inhibit IL-3 binding or function. Epitope mapping experiments using truncated IL-3R alpha-chain mutants and IL-3R alpha/GM-CSFR alpha chimeras revealed that 31 amino acids in the N-terminus of IL-3R alpha were required for MoAb 7G3 binding. MoAb 7G3 may be of clinical significance for antagonizing IL-3 in pathologic conditions such as some myeloid leukemias, follicular B-cell lymphoma, and allergy. Furthermore, these results implicate the N-terminal domain of IL-3R alpha in IL-3 binding. Since this domain is unique to the IL-3/GM-CSF/IL-5 receptor subfamily, it may represent a novel and common binding feature in these receptors.
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PMID:Monoclonal antibody 7G3 recognizes the N-terminal domain of the human interleukin-3 (IL-3) receptor alpha-chain and functions as a specific IL-3 receptor antagonist. 854 80

Leukemia inhibitory factor (LIF), interleukin 6 (IL-6) and IL-8 are important regulators of inflammation and hematopoiesis. Human bone marrow stromal cells regulate marrow hematopoiesis by secreting cytokines. By using reverse-transcriptase polymerase chain reaction (RT-PCR), we demonstrate that human bone marrow stromal cells constitutively express LIF, IL-6 and IL-8 transcripts. By using specific ELISAs, we found that their spontaneous productions of LIF, IL-6 and IL-8 are elevated in response to serum and after stimulation with the pro-inflammatory cytokines IL-1alpha and TNF-alpha. The anti-inflammatory cytokine IL-4 reduces their serum- and cytokine-induced LIF secretion. By contrast, IL-4 stimulates their serum- and IL-1alpha-induced IL-6 synthesis. IL-4 has no effect on the serum-induced IL-8 synthesis by marrow stromal cells, but stimulates their cytokine-induced IL-8 production. The anti-inflammatory cytokine IL-10 has no effect on the serum- and cytokine-induced LIF, IL-6 and IL-8 synthesis by bone marrow stromal cells. RT-PCR experiments reveal the presence of IL-4 receptor alpha-chain mRNA and IL-10 receptor mRNA in cultured bone marrow stromal cells. The differential regulation by IL-4 of two related cytokines, such as LIF and IL-6, and the enhanced effect of this 'anti-inflammatory' cytokine on IL-6 and IL-8 synthesis highlight the tightly controlled regulation and the complexity of the cytokine production within the human bone marrow.
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PMID:Interleukin-4 (IL-4), but not IL-10, regulates the synthesis of IL-6, IL-8 and leukemia inhibitory factor by human bone marrow stromal cells. 1007 53

Dendritic cells (DC) represent the most powerful professional antigen-presenting cells (APC) in the immune system. The aim of the present study was to analyse, on a single-cell basis by multiparametric flow cytometry with simultaneous four-colour staining and a two-step acquisition procedure, the immunophenotypic profile and cytokine production of DC from 67 normal whole peripheral blood (PB) samples. Two clearly different subsets of HLA-II+/lineage- were identified on the basis of their distinct phenotypic characteristics: one DC subset was CD33strong+ and CD123dim+ (0.16 +/- 0.06% of the PB nucleated cells and 55.9 +/- 11. 9% of all PB DC) and the other, CD33dim+ and CD123strong+ (0.12 +/- 0.04% of PB nucleated cells and 44.53 +/- 11.5% of all PB DC). Moreover, the former DC subpopulation clearly showed higher expression of the CD13 myeloid-associated antigen, the CD29 and CD58 adhesion molecules, the CD2, CD5 and CD86 costimulatory molecules, the CD32 IgG receptor and the CD11c complement receptor. In addition, these cells showed stronger HLA-DR and HLA-DQ expression and a higher reactivity for the IL-6 receptor alpha-chain (CD126) and for CD38. In contrast, the CD123strong+/CD33dim+ DC showed a stronger reactivity for the CD4 and CD45RA molecules, whereas they did not express the CD58, CD5, CD11c and CD13 antigens. Regarding cytokine production, our results show that while the CD33strong+/CD123dim+ DC are able to produce significant amounts of inflammatory cytokines, such as IL-1beta (97 +/- 5% of positive cells), IL-6 (96 +/- 1.1% of positive cells), IL-12 (81.5 +/- 15.5% of positive cells) and tumour necrosis factor-alpha (TNF-alpha) (84 +/- 22.1% of positive cells) as well as chemokines such as IL-8 (99 +/- 1% of positive cells), the functional ability of the CD123strong+/CD33dim+ DC subset to produce cytokines under the same conditions was almost null. Our results therefore clearly show the presence of two distinct subsets of DC in normal human PB, which differ not only in their immunophenotype but also in their functionality, as regards cytokine production.
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PMID:Extensive characterization of the immunophenotype and pattern of cytokine production by distinct subpopulations of normal human peripheral blood MHC II+/lineage- cells. 1059 57

An excess of the proinflammatory substance IL-18 is present in joints of patients with rheumatoid arthritis (RA), and expression of IL-18 receptor (IL-18R) regulates IL-18 bioactivity in various cell types. We examined the expression of IL-18R alpha-chain and beta-chain and the biologic effects of IL-18 in fibroblast-like synoviocytes (FLS) after long-term culture. The presence of both IL-18R chains was a prerequisite for IL-18 signal transduction in FLS. However, all FLS cultures studied were either resistant or barely responsive to IL-18 stimulation as regards cell proliferation, expression of adhesion molecules ICAM-1 and vascular cell adhesion molecule (VCAM)-1, and the release of interstitial collagenase and stromelysin, IL-6 and IL-8, prostaglandin E2, or nitric oxide. We conclude that the presence of macrophages or IL-18R+ T cells that can respond directly to IL-18 is essential for the proinflammatory effects of IL-18 in synovitis in RA.
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PMID:Expression of interleukin-18 receptor in fibroblast-like synoviocytes. 1187 50

Meningococcal lipopolysaccharide (LPS) is of crucial importance for the pathogenesis of invasive infection. We show that sialylation and elongation of the alpha-chain effectively shields viable unencapsulated Neisseria meningitidis from recognition by human dendritic cells (DC). In contrast, beta- and gamma- chain of the LPS carbohydrate moiety play only a minor role in the interaction with DC. The protective function of the LPS for the bacteria can be counteracted in vivo by phase variation of the lgtA gene encoding LPS glycosyltransferase A. Capsule expression protects N. meningitidis efficiently from recognition and phagocytosis by DC independent of the LPS structure. Despite the significant impact of LPS composition on the adhesion and phagocytosis of N. meningitidis no differences were found in terms of cytokine levels secreted by DC for IL1-beta, IL-6, IL-8, TNF-alpha, IFN-gamma and GM-CSF. However, significantly lower levels of the regulatory mediator IL-10 were induced by encapsulated strains in comparison to isogenic unencapsulated derivatives. IL-10 secretion was shown to depend on phagocytosis because poly alpha-2,8 sialic acid did not influence IL-10 secretion. The use of truncated LPS isoforms in vaccine preparations can therefore not only result in attenuation but also in more efficient targeting of DC.
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PMID:Carbohydrate composition of meningococcal lipopolysaccharide modulates the interaction of Neisseria meningitidis with human dendritic cells. 1609 19

Our aim was to develop an explant model to define more precisely the early response of bovine mammary epithelial cells to infection. Therefore we investigated the mRNA expression encoding for some soluble immunological factors in lipopolysaccharide (LPS)-treated bovine mammary gland explants. Explants were taken out from the mammary gland of eight lactating cows after slaughter then incubated with LPS (10 mug/ml) for 6 h. The mRNA expression of alpha-lactalbumin (alpha-la), various cytokines, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, and two immunoglobulin receptors, the neonatal Fc receptor (FcRn) and polymeric immunoglobulin receptor (pIGR), were assessed with qPCR before and after 3 h and 6 h of LPS challenge. Both immunoglobulin receptors and alpha-la increased at 3 h then recovered their initial level at 6 h whereas IL-1beta, IL-6 and IL-8 increased only after 6 h (P<0.05). Surprisingly, TNF-alpha transcripts did not show any regulation in response to the LPS treatment. We nevertheless concluded that our model was valid to examine the short-term response of mammary epithelial cell challenged with LPS.
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PMID:Use and relevance of a bovine mammary gland explant model to study infection responses in bovine mammary tissue. 1697 38

Aggregation of the alpha-chain of the high affinity IgE receptor (Fc epsilon RI alpha) on mast cells or basophils after cross-linking of receptor-bound IgE by its antigen or an anti-IgE antibody results in cell activation and release of inflammatory mediators. Omalizumab (Xolair), Novartis Pharmaceuticals; Genentech Inc.) is a recombinant humanized anti-IgE mAb developed for the treatment of severe allergic asthma. It complexes with free serum IgE, which prevents its binding to Fc epsilon RI and thereby interrupts the allergic cascade. Administration of an inhibitory anti-Fc epsilon RI alpha mAb may represent an alternative strategy to neutralize IgE-mediated receptor activation. In the present report, for the first time, we have performed direct side of side comparison between the inhibitory anti-Fc epsilon RI alpha mAb designated 15/1 and Omalizumab for their effects on human cord blood-derived mast cells. We provide the first evidence that both 15/1 mAb and Omalizumab efficiently inhibit Fc epsilon RI-mediated human mast cell responses in vitro (degranulation, activation, release of IL-8 and IL-13, phosphorylation of Akt) and that mAb 15/1 is a non-anaphylactogenic antibody, which compared to Omalizumab, displays markedly higher inhibitory potency in the presence of high IgE levels.
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PMID:Inhibition of human cord blood-derived mast cell responses by anti-Fc epsilon RI mAb 15/1 versus anti-IgE Omalizumab. 1736 11

Since interleukin (IL)-18 is a proinflammatory cytokine, mice lacking IL-18 or its ligand-binding receptor (IL-18R) should exhibit decreased cytokine and chemokine production. Indeed, production of IL-1alpha, IL-6, and MIP-1alpha was reduced in IL-18 knock-out (ko) mouse embryonic fibroblast (MEF)-like cells. Unexpectedly, we observed a paradoxical 10-fold increase in IL-1beta-induced IL-6 production in MEF cells from mice deficient in the IL-18R alpha-chain (IL-18Ralpha) compared with wild type MEF. Similar increases were observed for IL-1alpha, MIP-1alpha, and prostaglandin E2. Likewise, coincubation with a specific IL-18Ralpha-blocking antibody augmented IL-1beta-induced cytokines in wild type and IL-18 ko MEF. Stable lines of IL-18Ralpha-depleted human A549 cells were generated using shRNA, resulting in an increase of IL-1beta-induced IL-1alpha, IL-6, and IL-8 compared to scrambled small hairpin RNA. In addition, we silenced IL-18Ralpha with small interfering RNA in primary human blood cells and observed up to 4-fold increases in the secretion of lipopolysaccharide- and IL-12/IL-18-induced IL-1beta, IL-6, interferon-gamma, and CD40L. Mechanistically, despite increases in Stat1 and IL-6, induction of SOCS1 and -3 (suppressor of cytokine signaling 1 and 3) was markedly reduced in the absence of IL-18Ralpha. Consistent with these observations, activation of the p38alpha/beta and ERK1/2 MAPKs and of protein kinase B/Akt increased in IL-18Ralpha ko MEF, whereas the negative feedback kinase MSK2 was more active in IL-18 ko cells. These data reveal a role for SOCS1 and -3 in the seemingly paradoxical hyperresponsive state in cells deficient in IL-18Ralpha, supporting the concept that IL-18Ralpha participates in both pro- and anti-inflammatory responses and that an endogenous ligand engages IL-18Ralpha to deliver an inhibitory signal.
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PMID:Increased cytokine production in interleukin-18 receptor alpha-deficient cells is associated with dysregulation of suppressors of cytokine signaling. 1959 92

CD14 is a key recognition molecule of innate immune responses, interacting with several TLRs. TLR signaling cross-talks extensively with the complement system, and combined CD14 and complement inhibition has been proved effective in attenuating inflammatory responses. Pig models of human diseases have emerged as valuable tools to study therapeutic intervention, but suitable neutralizing Abs are rare. Undesired Fc-mediated functions, such as platelet activation and IL-8 release induced by the porcine CD14-specific clone Mil2, limit further studies. Therefore, an inert human IgG2/IgG4 hybrid C region was chosen for an rMil2. As revealed in ex vivo and in vivo pig experiments, rMil2 inhibited the CD14-mediated proinflammatory cytokine response similar to the original clone, but lacked the undesired Fc-effects, and inflammation was attenuated further by simultaneous complement inhibition. Moreover, rMil2 bound porcine FcRn, a regulator of t1/2 and biodistribution. Thus, rMil2, particularly combined with complement inhibitors, should be well suited for in vivo studies using porcine models of diseases, such as sepsis and ischemia-reperfusion injury. Similarly, the recombinant anti-human CD14 IgG2/4 Ab, r18D11, was generated with greatly reduced Fc-mediated effects and preserved inhibitory function ex vivo. Such Abs might be drug candidates for the treatment of innate immunity-mediated human diseases.
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PMID:Chimeric anti-CD14 IGG2/4 Hybrid antibodies for therapeutic intervention in pig and human models of inflammation. 2406 86


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