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

Products of an activated immune system may affect cells within the immune system as well as nonlymphoid cells in the local environment. Given the immunologically activated state of the intestinal tract, it is conceivable that locally produced cytokines could regulate epithelial cell function. To assess whether epithelial cells are targets for particular cytokines, we initiated studies on the binding of a panel of proinflammatory cytokines in freshly isolated epithelial cells from normal and inflammatory bowel disease (IBD) patients as well as in cell lines. Isolated intestinal epithelial cells (IEC) were stained with phycoerythrin-conjugated or biotinylated cytokines to determine the expression and density of receptors for IL-1beta, IL-6, granulocyte-macrophage CSF (GM-CSF), and TNF-alpha. Receptors for IL-1beta, IL-6, and GM-CSF were readily detectable in all epithelial cell preparations at levels equal to (GM-CSFR) or lower than those seen on monocytes. However TNFalpha-R were not detectable on freshly isolated IECs. Receptor density was greater in surface vs crypt epithelial cells, but no significant differences were seen between normal and IBD epithelial cells. Expression of IL-1R and IL-6R was enhanced by LPS and IFN-gamma. Functionally, IL-1beta enhanced proliferation of the IEC cell line, DLD1, whereas GM-CSF treatment of de-differentiated crypt-like DLD1 and HT29 cells resulted in enhanced expression of ICAM-1. Furthermore, TNF-alpha treatment enhanced the secretion of IL-8 and GRO-alpha in HT29 cells, but not in freshly isolated IEC cultures. The differential binding and function of proinflammatory cytokines on IEC support the hypothesis that these cytokines may be involved in normal physiological processes as well as in regulating mucosal immune responses.
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PMID:The regulation and functional consequence of proinflammatory cytokine binding on human intestinal epithelial cells. 975 92

The regulation and function of the CD44 family of surface glycoproteins were investigated in human monocyte-derived dendritic cells (DCs). Variant CD44 isoform transcripts encoding exons v3, v6, and v9 are differently regulated during the differentiation of monocytes into DCs. TNF-alpha treatment, which induces the maturation of DCs, up-regulates the expression of all v3-, v6-, and v9-containing isoforms examined. CD44 molecules are involved in the adhesion of DCs to immobilized hyaluronate (HA), and v3- and v6-containing variants participate in this function, whereas anti-CD44v9 mAbs were unable to inhibit DC adhesion to HA. The consequences of ligand binding to CD44 were examined by culturing DCs on dishes coated with HA or various anti-CD44 mAbs. HA, the anti-pan CD44 mAb J173, and mAbs directed against v6- and v9-containing (but not v3-containing) isoforms provoked DC aggregation, phenotypic and functional maturation, and the secretion of IL-8, TNF-alpha, IL-1beta, and granulocyte-macrophage CSF. In addition, IL-6, IL-10, and IL-12 were released by DCs stimulated with either J173 or HA, although these cytokines were not detected or were found only at low levels in the culture supernatants of DCs treated with anti-CD44v6 or anti-CD44v9 mAbs. Our study points to distinct capacities of the v3-, v6-, and v9-containing isoforms expressed by human DCs to mediate cell adhesion to HA and/or a signal inducing DC maturation and the secretion of cytokines.
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PMID:Adhesive and/or signaling functions of CD44 isoforms in human dendritic cells. 978 Jan 56

Endothelial cells, by virtue of their capacity to express adhesion molecules and cytokines, are intricately involved in inflammatory processes. Endothelial cells have been shown to express interleukin-1 (IL-1), IL-5, IL-6, IL-8, IL-11, IL-15, several colony-stimulating factors (CSF), granulocyte-CSF (G-CSF), macrophage CSF (M-CSF) and granulocyte-macrophage CSF (GM-CSF), and the chemokines, monocyte chemotactic protein-1 (MCP-1), RANTES, and growth-related oncogene protein-alpha (GRO-alpha). IL-1 and tumor necrosis factor-alpha (TNF-alpha) produced by infiltrating inflammatory cells can induce endothelial cells to express several of these cytokines as well as adhesion molecules. Induction of these cytokines in endothelial cells has been demonstrated by such diverse processes as hypoxia and bacterial infection. Recent studies have demonstrated that adhesive interactions between endothelial cells and recruited inflammatory cells can also signal the secretion of inflammatory cytokines. This cross-talk between inflammatory cells and the endothelium may be critical to the development of chronic inflammatory states. Endothelial-derived cytokines may be involved in hematopoiesis, cellular chemotaxis and recruitment, bone resorption, coagulation, and the acute-phase protein synthesis. As many of these processes are critical to the maturation of an inflammatory and reparative state, it appears likely that endothelial-derived cytokines play a crucial role in several diseases, including atherosclerosis, graft rejection, asthma, vasculitis, and sepsis. Genetic and pharmacologic manipulation of endothelial-derived cytokines provides an additional approach to the management of chronic inflammatory diseases.
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PMID:Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease. 1009 Mar 94

Monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein of 10 kDa (IP-10) are related members of the CXC chemokine subfamily that bind to a common receptor, CXCR3, and that are produced by different cell types in response to IFN-gamma. We have recently reported that human polymorphonuclear neutrophils (PMN) have the capacity to release IP-10. Herein, we show that PMN also have the ability to produce MIG and to express I-TAC mRNA in response to IFN-gamma in combination with either TNF-alpha or LPS. While IFN-gamma, alone or in association with agonists such as fMLP, IL-8, granulocyte (G)-CSF and granulocyte-macrophage (GM)-CSF, failed to influence MIG, IP-10, and I-TAC gene expression, IFN-alpha, in combination with TNF-alpha, LPS, or IL-1beta, resulted in a considerable induction of IP-10 release by neutrophils. Furthermore, IL-10 and IL-4 significantly suppressed the expression of MIG, IP-10, and I-TAC mRNA and the extracellular production of MIG and IP-10 in neutrophils stimulated with IFN-gamma plus either LPS or TNF-alpha. Finally, supernatants harvested from stimulated PMN induced migration and rapid integrin-dependent adhesion of CXCR3-expressing lymphocytes; these activities were significantly reduced by neutralizing anti-MIG and anti-IP-10 Abs, suggesting that they were mediated by MIG and IP-10 present in the supernatants. Since MIG, IP-10, and I-TAC are potent chemoattractants for NK cells and Th1 lymphocytes, the ability of neutrophils to produce these chemokines might contribute not only to the progression and evolution of the inflammatory response, but also to the regulation of the immune response.
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PMID:Gene expression and production of the monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein-10 (IP-10) chemokines by human neutrophils. 1020 39

The mechanism(s) underlying the release of stem/progenitor cells from bone marrow into the circulation is poorly understood. We hypothesized that matrix metalloproteinases (MMPs), especially gelatinases, which are believed to participate in the proteolysis of basement membranes and in the migration of leukocytes, may facilitate this process. First, we investigated whether CD34(+) stem/progenitor cells express gelatinases A (MMP-2) and/or B (MMP-9) and whether growth factors and cytokines (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], stem cell factor [SCF], macrophage colony-stimulating factor [M-CSF], interleukin-3 [IL-3], IL-6, IL-8, and tumor necrosis factor-alpha [TNF-alpha]) are able to modulate their expression. Next, we examined the transmigration of these stem/progenitor cells through reconstituted basement membrane (Matrigel) and its modulation by growth factors and cytokines. CD34(+) cells were obtained from steady-state bone marrow and peripheral blood (from leukapheresis products collected either in steady-state hematopoiesis or after mobilization with G-CSF plus chemotherapy or G-CSF alone). We found that peripheral blood CD34(+) cells, regardless of whether they were mobilized or not, strongly expressed both gelatinases (MMP-2 and MMP-9) in contrast to steady-state bone marrow CD34(+) cells, which did not. However, all the growth factors and cytokines tested could induce MMP-2 and MMP-9 secretion by the latter cells. Moreover, the stimulatory effects of G-CSF and SCF on both MMP-2 and MMP-9 secretion were found to be significantly higher in CD34(+) cells isolated from bone marrow than in those from peripheral blood. In addition TNF-alpha, GM-CSF, and IL-6 increased the secretion of a partially active form of MMP-2. Basal transmigration of bone marrow CD34(+) cells through Matrigel was lower than that of peripheral blood CD34(+) cells (P <.0001), but growth factors and cytokines increased it by 50% to 150%. Positive correlations were established between expression of gelatinases and CD34(+) cell migration (r >.9). The stimulatory effect of G-CSF was significantly greater on the migration of CD34(+) cells from bone marrow than on those from peripheral blood (P =.004). Moreover, CD34(+) cell migration was reduced to approximately 50% by antibodies to MMP-2 and MMP-9, tissue inhibitors of metalloproteinases (rhTIMP-1 and -2), and o-phenanthroline. TNF-alpha-induced gelatinase secretion and migration of CD34(+) cells and of clonogenic progenitors (colony-forming unit-granulocyte-macrophage [CFU-GM], burst-forming unit-erythroid [BFU-E], colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM], and colony-forming unit-megakaryocyte [CFU-MK]) were dose-dependent. Therefore, this study demonstrated that CD34(+) cells that are circulating in peripheral blood express both MMP-2 and MMP-9 and transmigrate through Matrigel. In contrast, CD34(+) cells from steady-state bone marrow acquire similar properties after exposure to growth factors and cytokines, which upregulate expression of gelatinases and transmigration of these cells when they enter the bloodstream. Hence, we suggest that growth factors and cytokines induce release of stem/progenitor cells from bone marrow into peripheral blood during mobilization, as well as during steady-state hematopoiesis, by signaling through gelatinase pathways.
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PMID:Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34(+) cells and their transmigration through reconstituted basement membrane. 1023 90

It has been suggested that mature neutrophils may play an essential role in the cascade of events leading to egress of stem cells from the bone marrow to the peripheral blood. To investigate further the role of mature neutrophils and of reactive oxygen intermediates (ROIs), known to be involved in the signal transduction of neutrophils, we used mice deficient in respiratory burst, and thus the production of ROIs, to study the involvement of this activation pathway in stem cell mobilization. B6 mice with chronic granulomatous disease (CGD) received either cyclophosphamide (200 mg/kg) on day 1 and granulocyte colony-stimulating factor (G-CSF) (250 microg/kg/d) on days 3-6 or a single dose of interleukin 8 (IL-8; 30 microg/mouse) as a mobilization regimen. On day 7, the number of stem and progenitor cells in blood and bone marrow was compared with control B6 animals (with intact respiratory burst). White blood cell counts, bone marrow cellularity and the frequency of granulocyte-macrophage colony-forming cells (GM-CFC), and cobblestone area-forming cells (CAFC) on days 7 (CAFC-7) and 28 (CAFC-28) were determined. After cyclophosphamide and G-CSF (CY + G), both mouse strains showed considerable mobilization of CAFC-7 and CFU-GM to the blood. Normal mice showed up to a 1905-fold increase in progenitors per ml blood, whereas CGD mice showed up to a 264-fold increase in blood progenitors. IL-8 also induced mobilization in both mouse strains. In addition to progenitors, primitive stem cells measured as CAFC-28 and as CAFC at day 35 were also mobilized by both mobilization protocols in normal as well as in CGD mice. In conclusion, respiratory burst and the subsequent signal transduction pathway do not appear to be required for mobilization of stem cells. Accordingly, neutrophils either are not involved in stem cell mobilization or other signalling pathways within neutrophils must exist that lead to the release of factors which activate stem cell egress from the bone marrow.
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PMID:Respiratory burst of neutrophils is not required for stem cell mobilization in mice. 1112 23

We report a case of unusual annular erythema associated with myelodysplastic syndrome (MDS). A 58-year-old male with MDS developed annular erythema on his back, scaly erythema on the dorsa of hands, and exudative erythema on his eyelids. Histological examination revealed a mononuclear cell infiltrate around vessels and follicles in the mid- to lower dermis. He had no history of treatment with granulocyte-colony-stimulating factor (G-CSF). Serum granulocyte-macrophage-colony-stimulating factor (GM-CSF) level was slightly elevated (5.84 pg/ml, normal < 2.0 pg/ml), whereas other cytokines including G-CSF, IL-6, and IL-8 were within normal limits. Skin manifestations were much improved by systemic mepitiostane, and serum GM-CSF level returned to normal levels.
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PMID:Unusual annular erythema associated with myelodysplastic syndrome. 1124 36

The aim of this study was to explore further the hypothesis that early stages of normal human hematopoiesis might be coregulated by autocrine/paracrine regulatory loops and by cross-talk among early hematopoietic cells. Highly purified normal human CD34(+) cells and ex vivo expanded early colony-forming unit-granulocyte-macrophage (CFU-GM)-derived, burst forming unit-erythroid (BFU-E)-derived, and CFU-megakaryocyte (CFU-Meg)-derived cells were phenotyped for messenger RNA expression and protein secretion of various growth factors, cytokines, and chemokines to determine the biological significance of this secretion. Transcripts were found for numerous growth factors (kit ligand [KL], FLT3 ligand, fibroblast growth factor-2 [FGF-2], vascular endothelial growth factor [VEGF], hepatocyte growth factor [HGF], insulinlike growth factor-1 [IGF-1], and thrombopoietin [TPO]); cytokines (tumor necrosis factor-alpha, Fas ligand, interferon alpha, interleukin 1 [IL-1], and IL-16); and chemokines (macrophage inflammatory protein-1alpha [MIP-1alpha], MIP-1beta, regulated upon activation, normal T cell expressed and secreted [RANTES], monocyte chemotactic protein-3 [MCP-3], MCP-4, IL-8, interferon-inducible protein-10, macrophage-derived chemokine [MDC], and platelet factor-4 [PF-4]) to be expressed by CD34(+) cells. More importantly, the regulatory proteins VEGF, HGF, FGF-2, KL, FLT3 ligand, TPO, IL-16, IGF-1, transforming growth factor-beta1 (TGF-beta1), TGF-beta2, RANTES, MIP-1alpha, MIP-1beta, IL-8, and PF-4 were identified in media conditioned by these cells. Moreover, media conditioned by CD34(+) cells were found to inhibit apoptosis and slightly stimulate the proliferation of other freshly isolated CD34(+) cells; chemo-attract CFU-GM- and CFU-Meg-derived cells as well as other CD34(+) cells; and, finally, stimulate the proliferation of human endothelial cells. It was also demonstrated that these various hematopoietic growth factors, cytokines, and chemokines are expressed and secreted by CFU-GM-, CFU-Meg-, and BFU-E-derived cells. It is concluded that normal human CD34(+) cells and hematopoietic precursors secrete numerous regulatory molecules that form the basis of intercellular cross-talk networks and regulate in an autocrine and/or a paracrine manner the various stages of normal human hematopoiesis.
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PMID:Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. 1134 33

Endothelial cells (ECs) are a critical component of the bone marrow stroma in the regulation of haemopoiesis. Recovery of bone marrow aplasia after radiation exposure depends, in part, on the repair of radiation-induced endothelial damage. Therefore, we assessed the ability of an irradiated human bone marrow EC line (TrHBMEC) to support transmigration, proliferation and differentiation of CD34+ bone marrow cells either irradiated or not in transendothelial migration or co-culture models. Radiation-induced EC damage was reflected by an increased release of soluble intercellular adhesion molecule (sICAM)-1 and platelet endothelial cell adhesion molecule (PECAM)-1. Irradiation of TrHBMECs with a 10 Gy dose strongly enhanced the transmigration of CD34+ cells, granulo-monocytic progenitors (CFU-GM) and erythroid progenitors (BFU-E). While ICAM-1 and PECAM-1 expression on irradiated TrHBMECs was increased, only antibodies against PECAM-1 inhibited the radiation-induced enhanced transmigration of haemopoietic cells. Irradiation of TrHBMECs (5-15 Gy) also increased proliferation and differentiation towards the granulo-monocytic lineage of co-cultured CD34+ cells, as well as colony formation by those cells and the production of interleukin 6 (IL-6), IL-8, granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF. Irradiated TrHBMECs were more capable of stimulating irradiated (1,2 Gy) CD34+ cells and haemopoietic progenitors than non-irradiated TrHBMECs. Together, these results suggest that, despite the radiation-induced damage, irradiated ECs may favour haemopoietic reconstitution after radiation exposure.
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PMID:Irradiation enhances the support of haemopoietic cell transmigration, proliferation and differentiation by endothelial cells. 1144 88

Interleukin-1 (IL-1) plays a major role in the regulation of bone marrow stromal cell function and hematopoiesis. It is known to induce secretion of the hematopoietic growth factors granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), IL-6, and IL-8 as well as IL-1 itself in stromal cells. We investigated the role of IL-1beta-mediated growth factor production in the human stromal cell line L88/5. Using liposome-mediated DNA transfer, two stromal cell transfectants that constitutively express IL-1beta antisense (AS) RNA were generated. Expression of IL-1beta AS RNA and IL-1beta RNA was determined by RT-PCR. The stromal cell transfectants were strongly impaired in their endogenous IL-1beta production, and this effect was present even when strong IL-1beta inducers, such as IL-1alpha and tumor necrosis factor-alpha (TNF-alpha), were used. Reduced endogenous IL-1beta levels had no effect on the constitutive production of IL-6, IL-8, and GM-CSF measured by ELISA. In contrast to lipopolysaccharide (LPS) stimulation, IL-1alpha-mediated stimulation of GM-CSF production was significantly reduced in AS transfectants. TNF-alpha induced GM-CSF production was also reduced. IL-6 and IL-8 production was increased in transfectants, suggesting a negative regulatory role of IL-1beta in L88/5. This new approach using AS technology to specifically target constitutive RNA expression will allow further characterization of the bone marrow cytokine network in normal and malignant hematopoiesis.
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PMID:Regulation of hematopoietic growth factor production by genetically modified human bone marrow stromal cells expressing interleukin-1beta antisense RNA. 1171 Sep 98


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