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)

In human peripheral blood mononuclear cells, ciliary neurotrophic factor (CNTF) weakly suppressed endotoxin-induced interleukin (IL)-1 and prostaglandin E2(PGE2). Suppression of PGE2 and IL-8 synthesis was significantly greater (up to 42.6%, P < 0.05) by adding a 10-fold molar excess of soluble CNTF receptor (sCNTFR alpha). In cultured human fibroblasts, CNTF at 12 micrograms/ml did not suppress IL-1 alpha-induced IL-8. However, in the presence of a 10-fold excess of sCNTFR alpha, 300 ng/ml of CNTF suppressed IL-1 alpha-induced IL-8 by 44%. Therefore, sCNTFR alpha can confer to CNTF anti-inflammatory properties in vitro. IL-6 which, like CNTF, utilizes the gp130 signal transducer, possesses similar inhibitory effects. That CNTF and IL-6 share gp130 as a receptor component suggests that gp130 mediates these anti-inflammatory responses.
 ...
PMID:Ciliary neurotrophic factor combined with soluble receptor inhibits synthesis of proinflammatory cytokines and prostaglandin-E2 in vitro. 795 80

The structural and functional relationships of the intracellular portion of mouse interleukin 1 receptor (muIL-1R) type I were examined with regard to activation of the human IL-8 gene in the Jurkat T cell line. C-terminal deletion mutations of muIL-1R revealed that the C-terminal boundary for receptor function is localized between 28 and 42 amino acids from the C-terminal end. The internal deletion mutants between amino acids 364 and 474 had a loss of activity, demonstrating the requirement for a large region of the mIL-1R cytoplasmic portion for receptor function. Amino acid substitution revealed that the putative nuclear localization elements (amino acids at 429-433, 523-527, and 507-519) and putative protein kinase C or A acceptor sites (Ser-431, Ser-509, Ser-528) do not participate in IL-1 signaling to induce IL-8 gene expression. A truncated mutation within the segment, which possesses homology with gp130, beta chain of IL-6R, or a point mutation of box 1- and box 2-like elements within the gp130 homologous segment, abolished the capacity to induce IL-8 gene expression, suggesting similar structural requirements in the cytoplasmic portion of several cytokine receptors.
 ...
PMID:Structure and function of the intracellular portion of the mouse interleukin 1 receptor (type I). Determining the essential region for transducing signals to activate the interleukin 8 gene. 851 84

The role of oncostatin M (OM) in modulating production of cytokines by connective tissue cells is largely unexplored. We have examined the effects of stimulating fibroblast cultures derived from human synovium and from normal lung with OM alone or in combination with IL-1, IL-1 alpha (or IL-1 beta) at 1 or 5 ng/ml, stimulated production of high levels of granulocyte-macrophage CSF (GM-CSF), IL-8, and IL-6 protein. At various concentrations (0.1-50 ng/ml), OM alone failed to significantly enhance protein or mRNA levels of GM-CSF, IL-8, IL-6, or G-CSF after 18 h of stimulation. When combined with IL-1 alpha or -beta, OM caused a dose-dependent inhibition of the IL-1-induced level of IL-8 and GM-CSF protein and mRNA expression, whereas IL-6 production was simultaneously enhanced. In contrast, when IL-6 or leukemia inhibitory factor (two other cytokines that share gp130 receptor components with OM) were used in a similar fashion in combination with IL-1 alpha, neither cytokine consistently altered the IL-1-induced levels of IL-8, GM-CSF, or IL-6. In addition, only OM and not IL-6 or leukemia inhibitory factor was able to induce STAT-1 nuclear factor binding to DNA in stimulated fibroblast extracts as measured by electrophoretic mobility shift assay. These results suggest that OM can significantly alter cytokine profiles of stimulated fibroblasts and may play a unique role in modulating cytokine production by these cells at sites of inflammation.
 ...
PMID:Oncostatin M inhibits IL-1-induced expression of IL-8 and granulocyte-macrophage colony-stimulating factor by synovial and lung fibroblasts. 859 83

Truncated forms of cytokine receptors have been regarded as modulators of the activity of their cognate ligands. In addition to inhibiting effects of their respective ligands, soluble receptors can also facilitate ligand-mediated signaling. Several studies have demonstrated that exogenous IL-6 in association with the soluble IL-6 receptor alpha (sIL-6Ralpha) can activate cells expressing the gp130 signal transducer lacking the specific, membrane-bound IL-6Ralpha. Since cell cultures of human dermal fibroblasts express high amounts of IL-6, we examined whether the addition of sIL-6Ralpha in association with endogenous IL-6 would be sufficient to stimulate these cells via gp130. As an early rapid signal we analyzed changes in intracellular free calcium concentrations ([Ca2+]i). Addition of sIL-6Ralpha induced an acute and transient increase in cytosolic free calcium concentrations in a dose-dependent fashion. This Ca2+-signal was abolished when cells were pretreated with anti-IL-6 or anti-gp130 antibodies. Using flow cytometric analysis we could demonstrate membrane-associated IL-6 and gp130, but not IL-6Ralpha on fibroblasts. We also analyzed MCP-1 and IL-8 expression as a response involved in the more recently recognized chemoattractant functions of fibroblasts, and found MCP-1 to be up-regulated, but not IL-8. These data suggest that sIL-6Ralpha binds to cell-associated, endogenous IL-6 produced by fibroblasts and this complex then activates the cells via gp130. This pathway of fibroblast activation by sIL-6Ralpha adds another dimension to the role of fibroblasts in the cytokine network.
 ...
PMID:Soluble IL-6 receptor induces calcium flux and selectively modulates chemokine expression in human dermal fibroblasts. 1038 37

Interleukin (IL) 6, an autocrine growth factor for mesangial cells, and chemokines, which are released from activated mesangial cells and induce leukocyte infiltration, play a critical role in the progression of immune system mediated renal diseases. Since the reciprocal relationship between IL-6 and chemokines in renal inflammation has been barely investigated, we have analyzed whether IL-6 (500 ng/ml), alone or in combination with the soluble form of its receptor (sIL-6R, 200 ng/ml), can induce normal human mesangial cells (NHMC) to release alpha and/or beta chemokines: MCP-1 (monocyte chemoattractant protein 1), IL-8, Rantes (regulated on activation, normal T cell expressed and secreted), and MIP-1alpha (macrophage inflammatory protein 1alpha). Whereas IL-6 or sIL-6R alone were ineffective in inducing significant chemokine release from NHMC, the simultaneous treatment with IL-6 and sIL-6R showed a significant interaction, leading to a strong synergic effect on MCP-1 synthesis and release without exerting any relevant activity on IL-8, Rantes, or MIP-1alpha. Consistently with the unresponsiveness to IL-6, mRNA and protein expression analysis of the two subunits which form the functional IL-6 receptor showed that NHMC express only the gp130 signal-transducing chain and not the subunit-specific IL-6R (gp80). These findings support an unexpected role of the IL-6 system in kidney inflammatory reactions through the selective regulation of monocyte recruitment.
 ...
PMID:Selective induction of MCP-1 in human mesangial cells by the IL-6/sIL-6R complex. 1064 81

Proinflammatory cytokines contribute to the development of inflammatory and neuropathic pain and hyperalgesia in many in vivo models. The rat skin model was used to investigate the effects of proinflammatory cytokines on the basal and heat-evoked release of calcitonin gene-related peptide from nociceptors in vitro. In contrast to the excitatory effects of cytokines observed in vivo, none of the cytokines tested evoked any calcitonin gene-related peptide (CGRP) release at normal skin temperature of 32 degrees C. However, the cytokines IL-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 but not IL-8 induced a pronounced and transient sensitization of the heat-evoked CGRP release from nociceptors in vitro. This heat sensitization was dose dependent, with EC(50) for IL-1 beta of 2.7 ng/ml and for TNF-alpha of 3.1 ng/ml. The maximum IL-1 beta effect reached almost 600% of the heat-evoked release, and the maximum TNF-alpha effect induced a rise in CGRP release of 350%. In contrast to IL-1 beta and TNF-alpha, IL-6 did not induce heat sensitization when applied alone but was only effective in the presence of soluble IL-6 receptor. This suggests a constitutive expression of signaling receptors for TNF and IL-1 beta and the signal transduction molecule gp130 but not IL-6 receptor or IL-8 receptor. Furthermore, the acute cytokine signaling observed in the present study was independent of transcriptional pathways because sensitization occurred on short latency in vitro and under conditions that excluded chemotactic accumulation of immune cells from blood vessels. Our results demonstrate that interleukins may play an important role in the initiation of heat hyperalgesia in inflammation and neuropathy.
 ...
PMID:Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin gene-related peptide release from rat skin. 1093 80

Thrombin is a procoagulant and proinflammatory molecule in vivo. In vitro, thrombin has been shown to induce endothelial activation, notably IL-8 secretion and adhesion molecule expression. In this study, we showed that thrombin may induce a new cascade leading from acute to chronic inflammation. Thrombin was able to induce the production of both IL-6 and monocyte chemotactic protein-1 (MCP-1) by HUVEC independently of IL-1alphabeta and TNF-alpha. Addition of physiological concentrations of exogenous soluble IL-6Ralpha (sIL-6Ralpha) to thrombin-activated HUVEC was sufficient to increase the amounts of MCP-1 produced, but not those of IL-8. These effects could be blocked by anti-IL-6 or anti-sIL-6Ralpha blocking mAb, demonstrating the existence of an autocrine loop of MCP-1 secretion, involving the IL-6/IL-6Ralpha/gp130 complex on HUVEC. In addition, we identified IL-8-activated neutrophils as a potential source of sIL-6Ralpha because IL-8 induced IL-6Ralpha shedding from the neutrophil membranes and increased in parallel sIL-6Ralpha concentrations in neutrophil supernatants. Furthermore, addition of neutrophils to thrombin-activated HUVEC significantly increased MCP-1 secretion, which could be decreased by blocking IL-6. Thus, thrombin-activated endothelium may induce a cascade of events characterized by IL-8 secretion, neutrophil local infiltration, and the release of IL-6Ralpha from neutrophil membranes. sIL-6Ralpha may then complex with IL-6 and increase the amount of MCP-1 produced by thrombin-activated endothelium, favoring monocyte infiltration, and the transformation of acute into chronic inflammation.
 ...
PMID:The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin. 1154 36

Oncostatin M (OSM) is a member of the interleukin (IL)-6 cytokine family and modulates inflammatory responses. Here we investigated the role of OSM as an immunoregulatory factor for human cerebral endothelial cells (HCEC). Using RT-PCR we detected transcripts of the receptor components involved in OSM signaling, gp130, OSM receptor (OSMR)-beta, and leukemia inhibitory factor receptor (LIFR), in HCEC. A parallel FACS analysis revealed surface expression of gp130 and OSMR-beta, but not of LIFR on these cells. Functionally, OSM upregulated intercellular adhesion molecule-1, but did not induce vascular cell adhesion molecule-1 in HCEC. Further, OSM upregulated IL-6 and monocyte chemoattractant protein (MCP)-1, whereas IL-8 was unaffected. Combined application of tumor necrosis factor (TNF)-alpha and OSM synergistically enhanced IL-6 and MCP-1 production, but downregulated TNF-alpha-induced IL-8. As OSM regulated molecules relevant in inflammatory brain diseases, we investigated its expression in normal and pathological human brains. OSM was detected by immunohistochemistry in brains from multiple sclerosis patients in microglia, reactive astrocytes, and infiltrating leukocytes, whereas in normal brains and noninflammatory neurological diseases. immunoreactivity was absent from the parenchyma. These data suggest that immunoregulatory functions in human cerebral endothelial cells may be a mechanism by which OSM participates in the pathophysiology of inflammatory brain disease.
 ...
PMID:Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions. 1170 38

Vasculitis, inflammation of the vessel wall, can be observed in acute and chronic inflammatory processes, in vascular rejection of allogeneic transplants and can be encountered as primary vasculitis of arterial, arteriolar, capillary and venular vessels. Although the numerous forms of vasculitis and their associations with different diseases result in a multitude of etiologic and pathogenetic factors there are pathogenetic factors common to several vasculitides. These include innate immunity factors, transcription factors such as NFkB, endothelial cytoprotective agents such as NO and anti-neutrophilic cytoplasmic auto-antibodies (ANCA). ANCA may be directed against several antigens, in the majority of cases against proteinase 3 and myeloperoxidase. The complex of proteinase 3 and ANCA leads to an increased expression of CD18, CD14 and an elevated synthesis of cytokines and chemokines such as interleukin 1, interleukin 8 in monocytes. In granulocytes generation of reactive oxygen species is found in addition. In both cells apoptosis finally occurs. ANCA may also bind to a surface glycoprotein (gp130) expressed on glomerular and peritubular endothelia in the kidney. Thus the activation of granulocytes, monocytes and endothelial cells by ANCA may be a critical step in the initiation phases of vasculitis. NO is cytoprotective for endothelial cells in small concentrations. Our group has shown in detailed studies that inhibition of endothelial NO synthase is detrimental and enhancement of activity of endothelial NO synthase is beneficial for allogeneic solid organ transplants. The transcription factor complex NFkB is a key regulatory transcription factor for the expression of genes and proteins associated with acute inflammatory processes and endothelialitis. Inhibition of NFkB activity by a decoy-oligonucleotide prevented activation of endothelial calls in reperfusion injury and vascular rejection. The complement system probably plays an essential role in the initiation and propagation phases of vasculitis. Specifically the pneumococcal C-polysaccharide-reactive protein (CRP), synthesized after trauma and infection, can potently activate the complement cascade which leads to an activation of endothelial cells with increased expression of adhesion molecules. The 4 shortly described pathogenetic mechanisms of vasculitis seem to be important and common factors for the generation and maintenance of vascular inflammation; nevertheless these factors are only part of the spectrum of different humoral and cellular responses in vasculitis. The described experimental investigations on endothelial damage and endothelialitis may lead to new therapeutic strategies in vasculitis.
 ...
PMID:[Vasculitis--aspect of cellular and molecular pathogenesis]. 1189 91

Recently, we identified that regulation of leukocyte recruitment by IL-6 requires shedding of the IL-6R from infiltrating neutrophils. In this study, experiments have examined whether other IL-6-related cytokines possess similar properties. Levels of oncostatin M (OSM) and leukemia inhibitory factor were analyzed in patients with overt bacterial peritonitis during the first 5 days of infection. Although no change in leukemia inhibitory factor was observed throughout the duration of infection, OSM was significantly elevated on day 1 and rapidly returned to baseline by days 2-3. The source of OSM was identified as the infiltrating neutrophils, and OSM levels correlated both with leukocyte numbers and i.p. soluble IL-6R (sIL-6R) levels. FACS analysis revealed that OSM receptor beta expression was restricted to human peritoneal mesothelial cells. Stimulation of human peritoneal mesothelial cells with OSM induced phosphorylation of gp130 and OSM receptor beta, which was accompanied by activation of STAT3 and secretion of CC chemokine ligand 2/monocyte chemoattractant protein-1 and IL-6. Although OSM itself did not modulate CXC chemokine ligand 8/IL-8 release, it effectively suppressed IL-1beta-mediated expression of this neutrophil-activating CXC chemokine. Moreover, OSM synergistically blocked IL-1beta-induced CXC chemokine ligand 8 secretion in combination with the IL-6/sIL-6R complex. Thus suggesting that OSM and sIL-6R release from infiltrating neutrophils may contribute to the temporal switch between neutrophil influx and mononuclear cell recruitment seen during acute inflammation.
 ...
PMID:Secretion of oncostatin M by infiltrating neutrophils: regulation of IL-6 and chemokine expression in human mesothelial cells. 1239 Dec 43


1 2 3 Next >>