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 CXC chemokine, IL-8, is a potent chemoattractant of neutrophils and binds to two distinct receptors, termed IL-8R1 and IL-8R2. These receptors share high affinity for IL-8, however, only IL-8R1 is specific for IL-8 whereas IL-8R2 binds other related chemokines, including GRO alpha with high affinity. Stable Jurkat transfectants were generated expressing either functional IL-8R1 or IL-8R2 (J-IL8R1 and J-IL8R2). Both J-IL8R1 and J-IL8R2 exhibited high affinity IL-8 binding (Kd 3-5 nM) with respective receptor densities of 23,000 +/- 3,000 and 18,500 +/- 1,500. Pre-treatment of both transfectants with 1.0 micrograms/ml B. pertussis toxin (PTx) resulted in inhibition of IL-8 mediated intracellular Ca2+ mobilisation and chemotaxis, without altering the receptor's affinity for its ligand. This indicates that both receptors couple to a PTx-sensitive G-protein. Further studies showed that IL-8R1 and IL-8R2 could mediate time-dependent phosphorylation of p42/p44 MAP-kinase. In both transfectants, phosphorylation was maximal at 1-2 min after IL-8 stimulation and could be inhibited by PTx. Stimulation of J-IL8R1 and J-IL8R2 with GRO alpha revealed that this chemokine was a more potent activator of MAP-kinase in J-IL8R2, an observation reflected in the high affinity binding of GRO alpha to IL-8R2. These studies indicate that chemokines are capable of activating protein kinases and with regards to PTx-sensitivity and MAP-kinase stimulation, no significant differences between IL-8R1 and IL-8R2 post-receptor signalling occur during cell activation by IL-8.
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PMID:A comparison of post-receptor signal transduction events in Jurkat cells transfected with either IL-8R1 or IL-8R2. Chemokine mediated activation of p42/p44 MAP-kinase (ERK-2). 775 May 73

Endometrial leukocyte subpopulations vary over the reproductive cycle, but no data exist on the mechanism regulating their recruitment into uterine tissue. This study has evaluated the role of progesterone in the recruitment of selected leukocyte populations in early pregnancy decidua. Decidua was collected from women in early pregnancy at the time of vacuum aspiration of the uterus 6, 12, 24 and 36 h after taking 200 mg mifepristone (RU486). Standard immunohistochemical techniques were employed to demonstrate the selected leukocyte populations in decidual tissue and these were analysed using imaged analysis. Fresh decidua was incubated in medium for 24 h and supernatants assayed for interleukin (IL-8) (neutrophil chemotactic factor) and MCP-1 (monocyte chemoattractant protein-1) content. Analysis of variance demonstrated a significant increase in tissue monocyte number in decidua 12-36 h after mifepristone administration. No significant changes in other leukocyte subpopulations were observed. Decidua IL-8 concentrations were significantly increased (P = 0.019) 6 h after mifepristone and decidual MCP-1 concentration rose (non-significant) and fell significantly (P = 0.029) between 6 and 12 h after mifepristone. Progesterone withdrawal may initiate a local cascade of events involving inflammatory mediators which in turn are responsible for the influx of monocytes. This influx may be essential in the process of shedding of endometrium or decidua since monocytes and neutrophils are important sources of proteases and collagenases. Furthermore, these cells are potential local sources of immunomodulatory cytokines.
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PMID:Sex steroid regulation of leukocyte traffic in human decidua. 894 39

We examined by RT-PCR the effect of a number of immunomodulatory compounds on cytokine gene expression at the level of mRNA in the HMC-1 human leukemic mast cell line. Resting cells expressed relatively low constitutive levels of mRNA for the cytokine genes IL-3, IL-4 and IL-8, and mRNA levels for each of these cytokines were significantly enhanced after 4-h stimulation with the calcium ionophore ionomycin. Treatment of the cells with the immunosuppressant CsA at 10(-5) M produced a significant inhibition of ionomycin-induced expression of IL-3, IL-4 and IL-8 mRNA, and at 10(-6) M produced a significant inhibition of induced expression of IL-3 and IL-8 but not IL-4. At both concentrations of CsA, expression of IL-3 was inhibited to a greater extent than that of the other two cytokines. Treatment of the cells with the corticosteroid DEX at 10(-5) M but not 10(-6) M significantly reduced the ionomycin-induced expression of IL-3 but not IL-4 or IL-8 mRNA. Progesterone and methotrexate were both inactive in modulation of induced cytokine expression in this cell line. In conclusion, this study shows that cytokine expression, particularly of IL-3, is inhibited in a human mast cell line by CsA and DEX. These findings may be relevant to the anti-allergic action of these drugs.
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PMID:The effects of cyclosporin A, dexamethasone and other immunomodulatory drugs on induced expression of IL-3, IL-4 and IL-8 mRNA in a human mast cell line. 902 May 23

Activation of the extracellular signal-regulated kinase (ERK) pathway has been shown to occur in monocytes following stimulation with LPS. However, the importance of this event for monocyte function is not clear. To address this issue, we used the novel MAP/ERK kinase (MEK) inhibitor, U0126. Stimulation of monocytes with LPS resulted in activation of the mitogen-activated protein kinase (MAPK) family members ERK, Jun NH2-terminal kinase (JNK), and p38. Treatment of monocytes with LPS in the presence of U0126 blocked the activation of ERK1 and ERK2. However, the activation of Jun NH2-terminal kinase and p38 family members was not affected by the compound, confirming the selectivity of U0126. To examine the effects of MEK inhibition on monocyte function, we measured production of the cytokines IL-1, IL-8, and TNF, as well as PGE2. Monocytes treated with LPS in the presence of U0126 failed to release IL-1, IL-8, TNF, or PGE2. The failure to secrete IL-1 and TNF was due to decreased levels of mRNA. These results demonstrate that activation of MEK/ERK is critical for cytokine and PGE2 production by monocytes in response to LPS.
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PMID:Inhibition of MAP kinase kinase prevents cytokine and prostaglandin E2 production in lipopolysaccharide-stimulated monocytes. 982 May 49

1. Intradermal (i.d.) injection of cytokines, IL-1beta and TNFalpha (5 ng, 60 and 30 min prior) produces a rapid onset up-regulation of des-Arg9-BK-mediated rat paw oedema. Here we analyse the mechanisms involved in des-Arg9-BK-induced oedema in animals pre-treated with IL-1beta or TNFalpha. 2. Co-injection of anti-IL-1beta, anti-TNFalpha and anti-IL-8 (50 ng) significantly inhibited des-Arg9-BK-induced oedema in animals pre-treated with IL-1beta (65, 37 and 42%) or TNFalpha (39, 64, 25%). IL-1 receptor antagonist (IRA, 100 microg) or IL-10 (10 ng) inhibited the oedema caused by des-Arg9-BK, in rats that had received either IL-1beta (67 and 63%) or TNFalpha (46 and 35%). 3. Co-injection of the PKC inhibitors, staurosporine (10 nmol) or RO 318220 (30 nmol) inhibited des-Arg9-BK-induced paw oedema (44 and 42% for IL-1beta and, 53 and 30% for TNFalpha, respectively). Genistein (tyrosine kinase inhibitor, 2.5 mg kg-1, s.c.) or PD 098059 (MAP-kinase inhibitor, 30 nmol) produced marked inhibition of des-Arg9-BK-induced oedema (58 and 39% for IL-1beta and 31 and 35% for TNFalpha respectively). 4. The NF-kappaB inhibitors TLCK (2 mg kg-1, i.p.) and PDCT (100 mg kg-1, i.p.) significantly inhibited the oedema of des-Arg9-BK in IL-1beta (27 and 83%) or TNFalpha (28 and 80%) pre-treated animals. 5. It is concluded that up-regulation of B1 receptors modulated by IL-1beta or TNFalpha involves the release of other cytokines, activation of PKC and tyrosine kinase pathways, co-ordinated with the activation of MAP-kinase and nuclear factor kappaB, reinforcing the view that B1 receptors may exert a pivotal role in modulating chronic inflammatory processes.
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PMID:In vivo B1 kinin-receptor upregulation. Evidence for involvement of protein kinases and nuclear factor kappaB pathways. 1048 16

To characterize mechanisms which may determine the fate of apoptotic cells, we investigated chemokine expression in apoptotic promonocytic U937 cells or peripheral blood mononuclear cells (PBMC). Exposure of U937 cells to etoposide (VP-16) or the nitric oxide (NO) donor DETA-NO, both inducers of apoptosis in these cells, was associated with increased expression of the chemokines IL-8 and macrophage inflammatory protein-1 alpha. Up-regulation of IL-8 mRNA expression by VP-16 or DETA-NO was observed as early as 4 h or 6 h, respectively, after onset of treatment and was still detectable after 19 h of exposure. A serine protease inhibitor prevented both VP-16-induced apoptosis and release of IL-8, whereas inhibition of p38 MAP kinases reduced IL-8 secretion only. Moreover, we observed that incubation with 2-chlorodeoxyadenosine (CdA) up-regulated release of IL-8 from adherent PBMC in parallel to induction of apoptosis. In these cells a modest but significant induction of TNF-alpha release by CdA was also detected. In addition, CdA augmented release of IL-8 from whole blood cultures. By facilitating adequate recruitment of phagocytes to sites of cell death, stress-induced up-regulation of chemokines associated with apoptosis may contribute to mechanisms aiming at efficient removal of apoptotic cells.
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PMID:Expression and release of chemokines associated with apoptotic cell death in human promonocytic U937 cells and peripheral blood mononuclear cells. 1054 Mar 34

Interleukin-8 (IL-8) is produced by human decidual cells in culture, and may play a role in the initiation of parturition. beta-endorphin is released in significant amounts into the maternal and fetal circulation during labour. The effect of beta-endorphin on IL-8 production by human chorio-decidual cells in culture was investigated. Mixed cells were obtained from the decidual surfaces of 35 term placentas. The cells were plated out at 10x10(6) cells per well in Roswell Park Memorial Institute 1640 culture medium. After 48 h the cells were washed and incubated with either plain culture medium (control), 1 micromol/l progesterone, 1-100 nmol/l beta-endorphin or 1 nmol/l N-acetyl beta-endorphin. After 48 h, IL-8 concentrations were measured in the supernatants by enzyme-linked immunosorbent assay (ELISA). Experiments were repeated in the presence of naloxone (1 micromol/l) and using calcium-deficient culture medium. Progesterone (P < 0.0002) and beta-endorphin (P < 0. 0005) significantly inhibited the production of IL-8. The inhibitory effect of beta-endorphin was blocked by naloxone and by using calcium-deficient medium. N-acetyl beta-endorphin had no significant effect on IL-8 production. These findings suggest that beta-endorphin has an inhibitory effect on IL-8 production by decidual cells, and that the effect is mediated via opioid receptors and is calcium-dependent.
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PMID:beta-endorphin inhibits the production of interleukin-8 by human chorio-decidual cells in culture. 1082 74

Exposure to fluorides can induce inflammatory reactions, cell cycle arrest, and apoptosis in different experimental systems. Fluorides are known G-protein activators, but less is known about fluoride effects downstream of G-protein activation. The aim of this study was to elucidate whether the induction of apoptosis by fluorides and inhibition of proliferation is mediated by MAP kinases in primary rat lung, alveolar type 2 cells and the human epithelial lung cell line A549. Sodium fluoride (NaF) induced apoptosis in both cell types but at different concentrations, with the primary cells being more sensitive to NAF: Proliferation of the type 2 cells and A549 cells was inhibited in the presence of NAF: NaF induced a prolonged activation of MAP kinase ERK. NaF also activated p38 and JNK in A549 cells for several hours (maximally 6-fold and 3-fold increase, respectively). Inhibition of ERK with the MEK1,2 inhibitor PD98059 increased apoptosis 2-fold, whereas the inhibitor of p38, SB202190, decreased the level of apoptotic cells by approximately 40%. SB202190 also inhibited apoptosis by almost 40% when ERK activity was reduced in the presence of PD98059. Neither PD98059 nor SB202190 did affect the NaF-induced inhibition of proliferation. These observations indicate that activation of MAP kinases p38 and possibly JNK are involved in NaF-induced apoptosis of epithelial lung cells, whereas ERK activation seems to counteract apoptosis in epithelial lung cells. In contrast, activation of ERK and p38 are not involved in NaF-induced inhibition of cell proliferation.
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PMID:Fluoride-induced apoptosis in epithelial lung cells involves activation of MAP kinases p38 and possibly JNK. 1129 78

The essential in pathogenesis of RA is induction of incorrect immunological response against synovial and connective tissue antigens, which depends of CD4+ T-cells activation by specific antigen. This stimulation leads to releasing Th1 lymphokines. The most important cytokine is TNF-alpha. An increased level of TNF-alpha, IL-1, IL-6, GM-CSF, IL-8 was observed in patients with RA. PDGF, FGF, TGF, C-X-C a chemokines (IL-GRO-alpha, ENA78) and CCb chemokines (RANTES, MCP1 MIP1 alpha) are also involved in synovial hyperplasia in RA. During a pregnancy a clinical improvement in women with RA is frequent. The reason of this fact is probably connected with Th2 predominance (IL-4, IL-10) caused by presence of fetal tissues. Specific, cell-mediated immunity is suppressed and changed to Th2 by progesterone and PGE2. During a pregnancy a higher sensitivity of lymphocytes to progesterone was found. Progesterone stimulates T cells to PIBF production, which decreases NK activity. Th2 cytokines (Il-6, IL-10, IL-13, TGF) are expressed on decidua and inhibit secretion of Th1 cytokines (IL-2, INF gamma, TNF-alpha, IL-1 alpha, IL-1 beta). Immunosuppression caused by pregnancy probably decreases inflammatory and destructive reactions in tissues women with RA. The first attack of this disease frequently observed during puerperium is connected with a high level of prolactin and a low of estrogens, which causes a increased release of IL-2 and has a main influence on initiation and increasing of inflammatory process in RA.
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PMID:[Current opinions on immunological processes in rheumatoid arthritis during pregnancy]. 1150 69

1. 3-Hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors (statins) prevent the progression of atherosclerosis by lowering cholesterol. However, the effect of statins on the synthesis of pro-inflammatory cytokines from endothelial cells has not yet been fully investigated. Here, we examined the effect of pravastatin, one of the statins, on IL-8 synthesis induced by thrombin in human aortic endothelial cells (AoEC) cultured with high glucose concentrations. 2. Pravastatin significantly decreased the IL-8 synthesis induced by thrombin. 3. Pravastatin inhibited the p44/42 MAP kinase activity induced by thrombin, but did not inhibit the p38 MAP kinase activity. 4. Translocation of ras protein from the cytosol to plasma membrane was inhibited by pravastatin. 5. Pravastatin inhibit the activator protein-1 activity, but did not inhibit the activation of IkappaB-alpha. 6. Dominant negative ras inhibited the p44/42 MAP kinase activity induced by PMA. 7. Our results suggest that pravastatin inhibits IL-8 synthesis by blocking the ras-MAP (p44/42) kinase pathway rather than nuclear factor-kappaB. Pravastatin may prevent atherosclerosis not only by lowering cholesterol levels, but also by suppressing IL-8 synthesis in AoEC through the inhibition of p44/42 MAP kinase, and this may be more beneficial in diabetic patients than in non-diabetics.
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PMID:Pravastatin suppresses the interleukin-8 production induced by thrombin in human aortic endothelial cells cultured with high glucose by inhibiting the p44/42 mitogen activated protein kinase. 1160 15


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