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 reported that rat peritoneal macrophages stimulated with LPS release a factor (MNCF) which induces neutrophil migration that is not blocked by glucocorticoids. The supernatant of macrophage monolayers stimulated with LPS was submitted to affinity chromatography on immobilized sugar columns. We observed that the D-gal binding fraction retained MNCF activity. This fraction, consisting of four protein components, was submitted to chromatography on Superdex 75, yielding a homogeneous preparation of the active component. MNCF has a MW of 54 KDa (gel filtration and SDS-PAGE) and pI < 4.0 (isoelectrofocusing and chromatofocusing). D-gal did not interfere with the behaviour of known interleukins (IL-1 beta, IL-6, IL-8 TNF-alpha), but blocked MNCF activity in an in vitro migration assay. The present results reinforce our previous suggestion that MNCF may correspond to a novel monokine which induces neutrophil migration through a direct mechanism involving the D-gal binding site of the molecule.
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PMID:Macrophage-released neutrophil chemotactic factor (MNCF) induces PMN-neutrophil migration through lectin-like activity. 831 22

Historically, the neutrophil has been perceived as a terminally differentiated leukocyte with limited ability to produce de novo proteins. Furthermore, in the context of acute inflammation the activated neutrophil has been appreciated only for its ability to release various proteases, reactive oxygen, and arachidonic acid metabolites. Recently, the neutrophil has been shown to have the capacity to produce a number of cytokines that may be instrumental in orchestrating the progression of acute inflammation to a more chronic and specific immune response. These cytokines include IFN-alpha, M-CSF, G-CSF, TNF, IL-1, and IL-6. Our laboratory and others have shown that neutrophils produce IL-8 in response to LPS or a phagocytic challenge. Although these studies have shown the induction of IL-8 from polymorphonuclear neutrophils (PMN), relatively little is known regarding the regulation of PMN-derived IL-8. Because PMN and monocytes share the same stem cell, and monocyte-derived IL-8 is regulated by prostaglandin E2 (PGE2), glucocorticoids (dexamethasone; DEX) and the T-Lymphocyte-derived IL-4, we postulated that PMN-derived IL-8 production may be regulated in a similar manner. To test this hypothesis, PMN were isolated (> 99% pure) from peripheral blood and cultured in media with 5% FCS in the presence or absence of LPS (10 ng/ml; a concentration of LPS that induced the half-maximal production of PMN-derived IL-8) and in the presence or absence of DEX (10(-6) M to 10(-10) M), PGE2 (10(-6) M to 10(-10) M), or IL-4 (100 ng/ml to 100 pg/ml). PMN-derived IL-8 was measured using a specific sandwich ELISA. DEX and IL-4 in the presence of LPS were found to inhibit PMN-derived IL-8 in both a dose- and time-dependent fashion. DEX and IL-4 in concentrations of 10(-6) M and 10 ng/ml resulted in maximal inhibition of LPS-induced PMN-derived IL-8, respectively. Moreover, both DEX and IL-4 administration could be delayed 4 hr post-stimulation with LPS and result in significant suppression of PMN-derived IL-8. Interestingly, in contrast to the regulation of monocyte-derived IL-8 by PGE2, PGE2 treatment of PMN failed to inhibit the generation of LPS-induced IL-8. Northern blot analysis of steady-state IL-8 mRNA demonstrated that both DEX and IL-4 treatment of PMN resulted in a 40 and 52% reduction in LPS-stimulated PMN-derived IL-8 mRNA, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of neutrophil-derived IL-8: the role of prostaglandin E2, dexamethasone, and IL-4. 834 1

We recently found that normal human sera contain IgG antibodies against two chemoattractants, neutrophil attractant protein-1 (NAP-1/IL-8) and monocyte chemoattractant protein-1 (MCP-1), as well as immune complexes of these proteins. Intravenously administered LPS was reported to cause a sharp rise in serum NAP-1 concentration. Our study was designed to determine if LPS also caused an increase in MCP-1 and to measure associated changes in concentrations of antibody and immune complex. LPS caused a rise to peak within 2 to 3 h in serum concentrations of free NAP-1 and MCP-1, followed by an almost equally rapid fall toward base-line levels by about 5 h postinjection. MCP-1 concentration in sera from the 11 subjects rose to a peak of 330 +/- 52 pM. The peak value for NAP-1 was 80 +/- 11 pM. In 10 of the 11 subjects, free IgG autoantibody to MCP-1 decreased from a mean pre-LPS value of 1820 +/- 660 pM to a mean low of 53% of the respective initial values. Corresponding data for IgG anti-NAP-1 were a pre-LPS concentration of 216 +/- 7 pM, which decreased to a mean low of 44% of the respective initial values. The finding in some subjects of a rapid rise in free antibody after the nadir suggests the possibility of acute regulation of autoantibody secretion rates. Although the results suggested that LPS-induced chemoattractant combined with free antibody, serum concentrations of MCP-1-IgG or NAP-1-IgG did not increase, which points to an as yet unknown mechanism for trapping and elimination of the immune complexes.
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PMID:Neutrophil attractant protein-1 and monocyte chemoattractant protein-1 in human serum. Effects of intravenous lipopolysaccharide on free attractants, specific IgG autoantibodies and immune complexes. 837 79

The aim of this study was to evaluate by cytofluorimetry, the phenotype and the activation of alveolar macrophages (CD14; CD33; CD44; CD54; CD23; HLA-DR) and, by radioimmunoassay, the "in vivo and in vitro" macrophage secretory pattern (IL-1 alpha; IL-1 beta; IL6; IL8; PGE2; PGD-1 alpha; TXB2; LTB4) in atopic patients with mild asthma in intercritical phase and with bronchial hyperreactivity (PD20 FEV1 = 377 +/- 262.8 micrograms). In asthmatic patients we have demonstrated that the number of cells recovered in BALF expressing the phenotypic features (CD14; CD33; HLA-DR; CD23; CD44; CD54) was larger than in control subjects. By analysing the culture medium of unstimulated and LPS-stimulated alveolar macrophages from asthmatic and normals we have demonstrated a greater production of IL-1 beta (p = 0.005) and IL-8 (p = 0.005) in the first group than in one second, as confirmed by a Wilcoxon test. Concerning the secretory pattern in BALF of asthmatic patients we obtained similar results, showing a significant IL-1 beta (p = 0.005) and IL-8 (p = 0.002) increase suggesting a persistent cellular activation. On the contrary we could not show any significant increase of IL-1 alpha (p = 0.31) and IL-6 (p = 0.22). The cellular activation was confirmed by increased levels of different chemical mediators such as TXB2 (p = 0.005); LTB4 (p = 0.004); PGE2 (p = 0.007); PGF-1 alpha (p = 0.008) which were recovered from BALF of asthmatic patients compared to normal subjects. In conclusion alveolar macrophages play an important role in the pathogenesis of asthma because of the presence of cytokines and mediators in BALF and in the supernatant of alveolar macrophage cultures.
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PMID:Phenotypic features and secretory pattern of alveolar macrophages in atopic asthmatic patients. 838 56

Fibroblasts play an indirect augmenting effector role in the inflammatory response by releasing growth and differentiation factors and other inflammatory mediators after activation by inflammatory cytokines such as interleukin (IL)-1, but whether direct activation occurs by exogenous agents such as endotoxin (lipopolysaccharide, LPS) remains controversial. Using a number of primary human airways tissue-derived fibroblast lines, we demonstrate that in contrast to IL-1 alpha, LPS significantly induced gene expression and production of granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-8, and IL-6 only in nasal but not bronchial or lung tissue-derived fibroblasts. Enhanced expression was dose- and time-dependent, and the minimal stimulatory dose was 10 ng LPS/ml. Polymyxin B entirely abrogated increased cytokine expression by LPS. Actinomycin D treatment largely inhibited expression, and LPS markedly increased an IL-6 gene promoter-driven luciferase reporter response in transfected nasal fibroblasts, suggesting enhanced expression may involve transcriptional regulation. Secondary protein or IL-1 synthesis requirement seemed unlikely since cycloheximide superinduced LPS-stimulated cytokine expression and anti-IL-1 alpha/beta antibodies failed to abrogate the response. Thus our data show that GM-CSF, IL-8, and IL-6 are directly inducible in nasal fibroblasts by LPS, and establish heterogeneous responsiveness to LPS by different fibroblast populations in the airways.
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PMID:Lipopolysaccharide induces expression of granulocyte/macrophage colony-stimulating factor, interleukin-8, and interleukin-6 in human nasal, but not lung, fibroblasts: evidence for heterogeneity within the respiratory tract. 839 62

Serum proteins play an important role in LPS-induced cell activation. The LPS binding protein (LBP) enhances cellular responses to LPS, whereas the polymorphonuclear leukocyte product bactericidal/permeability-increasing protein (BPI) inhibits LPS-induced cell activation. In this study the influences of LBP and BPI, two proteins with opposite effects, but with considerable sequence homology, on LPS-induced mononuclear phagocytic cell cytokine release was studied. LBP was shown to enhance LPS-induced TNF-alpha, IL-6, and IL-8 release by mononuclear phagocytic cells, whereas BPI inhibited the release of these cytokines. Furthermore, the effects of LBP and BPI on LPS-induced cytokine release by mononuclear phagocytic cells were shown to be counteractive. BPI interfered with the enhancing effect of LBP on the LPS-induced cytokine release. At high LBP to BPI ratios, BPI could no longer inhibit LBP-induced enhancement. In accordance, increasing concentrations of BPI abrogated the LBP effect. Next, it was shown that LBP and BPI compete for binding to LPS by using an assay system that detects binding of free BPI to an anti-BPI mAb. LPS prevented binding of BPI to anti-BPI mAb, whereas preincubation of LPS with LBP prevented the LPS-induced inhibition. Also, it was observed that both BPI and LBP inhibited LPS activity in the chromogenic LAL assay. We conclude from this study that LBP and BPI have counteractive effects on LPS-induced mononuclear phagocytic cell cytokine release by competing for binding to LPS.
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PMID:Antagonistic effects of lipopolysaccharide binding protein and bactericidal/permeability-increasing protein on lipopolysaccharide-induced cytokine release by mononuclear phagocytes. Competition for binding to lipopolysaccharide. 840

Neutrophils are possibly involved in the pathogenesis of various lung diseases through the release of numerous mediators. In the present study, we studied the regulation of IL-8 gene induction and protein secretion in human blood neutrophils. Northern blot analysis revealed that LPS increased IL-8 mRNA levels in neutrophils, with a maximal fivefold increase by 2 h. IL-8 mRNa levels returned to baseline values within 12 h. In contrast, LPS-stimulated monocytes demonstrated a sustained increase of IL-8 mRNA levels for more than 24 h. TNF-alpha, IL-1 beta, and phorbol myristate acetate also increased IL-8 mRNA levels in neutrophils. Immunohistochemical analysis confirmed that IL-8 was localized within stimulated neutrophils. IL-8 secretion by neutrophils and monocytes was quantified using a specific ELISA for IL-8. Resting neutrophils secreted minimal IL-8 activity. However when cells were stimulated with LPS, TNF-alpha, or IL-1B, neutrophils secreted IL-8. IL-8 secretion was most marked during the first 2 h after stimulation and decreased thereafter. In contrast, monocytes maintained a high rate of IL-8 secretion over 12 h. Although a single monocyte secreted 70-fold more IL-8 than did a single neutrophil after 4 h of incubation, the high abundance of neutrophils in peripheral blood made the neutrophil-secreted IL-8 more significant. During the first 2 h, neutrophils secreted approximately 40% of the IL-8 released by monocytes in the same volume of blood. This ratio decreased to 9% after 12 h. Neutrophil-secreted IL-8 may play an autocrine or paracrine role during the initial stage of inflammation.
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PMID:Regulation of neutrophil interleukin 8 gene expression and protein secretion by LPS, TNF-alpha, and IL-1 beta. 843 97

Macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta all belong to the newly recognized "chemokine" superfamily of structurally related, activation-inducible cytokines with inflammatory and growth regulatory activities. We report the isolation and sequencing of genomic clones for murine MIP-2 and murine MIP-1 beta, and analyze their regulatory sequences in comparison with each other and with several other members of the chemokine family. The murine (mu)MIP-2 genomic clone displays the canonical four exon/three intron structure typical of other genes in the chemokine alpha subfamily (e.g., IL-8). Potential cis regulatory elements in the proximal promoter region were highly conserved between muMIP-2 and its three most closely related human homologs: human (hu)GRO-alpha, huGRO-beta, and huGRO-gamma. A mouse macrophage cell line, RAW 264.7, was transfected with a growth hormone reporter construct driven by a proximal fragment of the muMIP-2 5' promoter, and nested deletion mutant analysis localized the LPS responsive element to a region that contains a conserved NF kappa B consensus motif and lies 51 to 70 bp 5' from the transcription start site. In contrast to that of MIP-2, the muMIP-1 beta genomic clone exhibited the three exon/two intron structure characteristic of the chemokine beta family members (e.g., MCP-1). A comparison of the promoters for muMIP-1 beta and muMIP-1 alpha reveals a conserved CK-1 element, but transient expression studies in RAW 264.7 macrophages with proximal fragments of either the muMIP-1 beta or the muMIP-1 alpha 5' promoter fused to a human growth hormone reporter gene link LPS-inducibility in both to promoter segments near to, but not identical with, the consensus CK-1 sequence. Proximal 5' promoter fragments cloned from both the MIP-1 alpha and MIP-1 beta genes unexpectedly conferred constitutive expression on the fused reporter gene sequences in macrophage-like cells, but initial 5' deletion analysis did not link this responsiveness to known sequence motifs. The muMIP-1 beta promoter, but not the muMIP-1 alpha promoter, was constitutively active in B16 mouse melanoma cells, and both promoters were active in the myelomonocytic cell line WEHI 3B(A)d-, the muMIP-1 alpha promoter being three times stronger.
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PMID:Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines. 849 1

1. LPS phase I trial revealed MTD I of 1.0 ng/kg body weight and MTD II of 5.0 ng/kg body weight, the latter given together with ibuprofen (1,600 mg). 2. LPS phase II trial, using 4,0 ng/kg body weight plus ibuprofen in a biweekly schedule didn't show any response in patients with non-small cell lung cancer but 1 CR and 2 PR (13% response rate) in colorectal cancer patients. 3. The LPS tolerance is specific for each cytokine and mediator in regard to the kinetic and degree of its development. INF-gamma prevents the tolerance development to several cytokines with the exception of IL-8. 4. No tolerance was found in cell adhesion, phospholipase A2, and soluble TNF receptor I and II. Priming of ex vivo cytokine production of cytokines was found in mononuclear cells. 5. Synthetic LPS partial structure SDZ-MRL 953 (I) induces a cytokine pattern, which is profoundedly different from that of LPS, (II) with an inverse TNF to G-CSF relation, (III) is (without any ibuprofen treatment) remarkably low toxic, (IV) and downregulates the TNF-response to LPS markedly.
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PMID:Endotoxin (Salmonella abortus equi) in cancer patients. Clinical and immunological findings. 852 30

The emigration of peripheral blood monocytes into the interstitium allows for contact with a variety of surfaces which may provide signals important for monocyte function in both normal and inflammatory states. In the present study, we examined the effect of adherence to an endothelial cell-derived basement membrane and to collagen I, the major collagen of the interstitium, on monocyte release and gene expression of the potent chemotactic cytokine Interleukin-8 (IL-8). We further evaluated neutrophil chemotactic activity of the conditioned media containing antigenic IL-8 from monocytes adherent to these same surfaces. Elutriation-purified monocytes were adhered for 1 hour to plastic tissue culture wells either uncoated (PL) or coated with bovine serum albumin (BSA), collagen type I (C-I), or endothelial cell-derived basement membrane (BM). Following removal of nonadherent cells, monocytes were further incubated in a serum-free media for 18 hours in the presence or absence of lipopolysaccharide (IPS). Following 18 hrs of incubation there were significantly less monocytes remaining adherent to BM when compared to other surfaces tested. In the absence of LPS, adherent monocytes released significant amounts of IL-8 that was not surface specific. In the presence of LPS, monocytes adherent to BM released significantly more IL-8, when corrected for adherent cell number, than monocytes adherent to PL, BSA, or C-I. Conditioned media from adherent monocytes expressed IL-8 dependent neutrophil chemotactic activity that was not influenced by the surfaces tested. Northern blot analysis indicated greater induction for IL-8 mRNA by monocytes adhered to BM after 18 hrs in the presence of LPS. These results suggest that monocyte adherence to the subendothelial basement membrane provides a priming signal for the induction and secretion of the chemotactic cytokine IL-8 in response to inflammatory stimuli.
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PMID:Monocyte adherence to the subendothelial basement membrane increases interleukin-8 gene expression and antigen release. 854 67


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