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)

The locomotor capacity of human lymphocytes is cell cycle-related. Many small blood lymphocytes are non-motile but acquire locomotor capacity in G1 on appropriate activation with e.g. anti-CD3 antibody (aCD3) for T cells, or interleukin-4 (IL-4) for B cells. Once this capacity is acquired, the cells can then respond by polarization and locomotor to chemoattractants such as IL-8 or foetal calf serum (FCS). These two stages in the locomotor process were distinguished by the use of two inhibitors, FK506 and pertussis toxin. FK506 caused a dose-dependent inhibition of cell cycle-related induction of locomotor capacity both of anti-CD3-cultured T cells and IL-4-cultured B cells, with an ID50 of less than 1 ng per ml. This was measured in assays both of morphological polarization and of locomotion into collagen gels. FK506 has no effect on chemoattractant-induced polarization. Conversely, pertussis toxin has little inhibitory effect on growth-induced locomotor capacity, but is an effective inhibitor of the immediate polarization response following addition of FCS or IL-8 to lymphocytes either direct from blood or after overnight culture. These results suggest that different signalling pathways are involved in the two stages. Growth-related locomotor activation does not involve a pertussis toxin-sensitive G protein and may be signalled in the same way as other mitogen-induced events which are sensitive to FK506 and cyclosporin. On the other hand, the locomotor response to attractants, on this and earlier evidence, is transduced via a pertussis toxin-sensitive G protein. However, after prolonged (24-48 hr) culture in the presence of pertussis toxin, lymphocyte locomotor responses to attractants become insensitive to pertussis toxin.
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PMID:FK506 and pertussis toxin distinguish growth-induced locomotor activation from attractant-stimulated locomotion in human blood lymphocytes. 170 50

Recently, the keratinocyte IL-8/IL-8 receptor (IL-8R) pathway has been implicated in the pathogenesis of psoriasis, and there is evidence that the potent macrolide immune suppressant tacrolimus (formerly FK506) can inhibit this pathway in vitro. In this study, determination of the expression of cytokine mRNAs in lesional skin of patients with active disease by reverse transcriptase polymerase chain reaction revealed transcripts for IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), IL-6, IL-8, IL-8R, IL-10, interferon-gamma (IFN-gamma), IL-2R and transforming growth factor-beta (TGF-beta), but not IL-2 or IL-4. IL-8 was the only cytokine expressed in affected skin of all patients but not in clinically normal skin of healthy subjects. In seven CD4+ T cell clones propagated from the lesional skin of an untreated psoriasis patient, IL-8 was expressed by the skin-derived T lymphocytes and not by feeder cells (irradiated autologous blood lymphocytes); IL-1 beta, IL-2, IL-6 and IL-10 were also expressed by some or all of the T cell clones. IL-8 mRNA was not detected in the skin of any patient after the start of systemic tacrolimus therapy; IL-1 beta, IL-6 and IFN-gamma transcripts were also reduced. By 12 weeks, the mean psoriasis area and severity index (PASI) had decreased from 18.8 to 3.8, a reduction of 80%. In the same post-treatment biopsies, however, message for IL-8R persisted. Estimation of circulating IL-8 levels by enzyme immunoassay showed that all patients with detectable IL-8 before treatment had decreased levels in response to treatment with tacrolimus; reductions in PASI scores were accompanied by decreases in IL-8 levels, that varied both in rate and extent. Partial relapse, which in a minority of patients followed the initial period of remission, and was precipitated by drug dose reduction, was accompanied by an increase in circulating IL-8. These findings add credence to the view that the IL-8/IL-8R autocrine/paracrine pathway may be important in the pathogenesis of psoriasis. They further suggest that interference with IL-8 production and/or that of other key chemokines may be an important mechanism underlying the therapeutic efficacy of tacrolimus, and other agents such as cyclosporin A, with similar molecular actions.
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PMID:IL-8/IL-8 receptor expression in psoriasis and the response to systemic tacrolimus (FK506) therapy. 753 27

The present study was conducted to determine whether cyclosporin A (CsA) and FK506 could be effective in inhibiting the proliferation and cytokine secretion of normal human epidermal keratinocytes (NHEK). NHEK proliferation in the presence of CsA and FK506 at the concentrations 10(-9) to 10(-5) M at 24 and 48 h time points was measured colorimetrically by the MTS assay. CsA had inhibitory effects from 10(-6) to 10(-5) M, while FK506 had no effect, except for toxicity at the very highest concentrations (5 x 10(-6) M and higher). NHEK cells spontaneously secrete IL-8 (243.4 +/- 55.5 pg/ml), and this baseline level was augmented by TNF-alpha alone, or synergistically by TNF-alpha and IFN-gamma, which are thought to be secreted by T cells. Neither CsA nor FK506 had any significant effect on either spontaneous or cytokine-stimulated keratinocyte IL-8 production. Therefore, it is most likely that the two drugs indirectly inhibit the keratinocyte inflammatory response through their actions on T cells or other immunocompetent cells.
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PMID:The effects of cyclosporin A and FK506 on proliferation and IL-8 production of cultured human keratinocytes. 853 11

The present study was designed to investigate the in vitro effects of potential therapeutic agents on cytokine production by five HTVL-I-infected T cell clones (TCC) established from the ocular fluid of patients with HTLV-I uveitis. Each of the five HTLV-I-infected TCC was cultured at 1 x 10(6) cells/ml with or without an immunosuppressive agent (hydrocortisone, FK506, rapamycin, indomethacin, or prostaglandin E2) for 22 hr in humidified 5% CO2 in air at 37 C. The production of various cytokines in the culture supernatant from each TCC was measured by ELISA. The HTLV-I-infected TCC produced high amounts of IL-1 alpha, IL-3, IL-6, IL-8, TNF-alpha, IFN-gamma, and GM-CSF, and low but significant levels of IL-2 and IL-10 without any stimuli. Hydrocortisone severely depressed the production by these TCC of all the cytokines except for IL-2, which was slightly increased. Prostaglandin E2 depressed the production of IL-1 alpha, while it up-regulated the production of IL-6, TNF-alpha, and IFN-gamma. Rapamycin depressed the production of IL-6 and TNF-alpha, and FK506 depressed the production of TNF-alpha. Hydrocortisone also severely depressed the cytokine production by PHA-stimulated peripheral blood mononuclear cells obtained from healthy volunteers. Of the immunosuppressive agents tested, hydrocortisone exhibited the strongest suppression of cytokine production by HTLV-I-infected TCC. This result was in agreement with the in vivo effects of hydrocortisone in patients with HTLV-I uveitis. These TCC will be useful in investigating the effects of potential therapeutic agents for HTLV-I uveitis in vitro.
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PMID:In vitro effects of immunosuppressive agents on cytokine production by HTLV-I-infected T cell clones derived from the ocular fluid of patients with HTLV-I uveitis. 880 2

Knowledge of the aetiology and pathogenesis of the inflammation in ulcerative colitis and Crohn's disease is still insufficient. It is thought that some antigen is the trigger which induces a chain of immune reactions but the origin of this antigen has not so far been elucidated. In theory, an antigen-presenting cell forms a complex with endotoxin-derived peptides as antigen. T-helper lymphocytes recognize this complex, are activated and start to produce cytokines. For inflammatory bowel diseases (IBD) the most important cytokines identified are interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), gamma-interferon (G-IFN), and tumor necrosis factor-alpha (TNF-alpha). Inhibition of these cytokines can be achieved by administration of cyclosporine, which inhibits the function of T-helper lymphocytes. Orally, intravenously, and locally administered cyclosporine is able to improve the disease activity in ulcerative colitis and Crohn's disease, but its use is limited because of side-effects. The novel immunosuppressant FK506 has comparable actions to cyclosporine in regulating cytokine production and may even be more effective than cyclosporine. The receptor antagonist of IL-1 (IL-1ra) competitively binds to the IL-1 receptor located on several lymphocytes. Treatment of animals with IL-1ra has been successful and clinical trials using recombinant IL-1ra are underway in IBD. Antibodies against alphaIL-2r have also been used successfully in animal studies. No experience with this substance has been obtained in man. The use of alpha-interferon seems to be effective in some patients with Crohn's disease. CD4 and CD8 molecules on lymphocytes are needed to form the interaction between antigen, antigen-presenting cell, and lymphocytes. Specific monoclonal antibodies against CD4 are successfully used in patients with active ulcerative colitis and Crohn's disease. TNF-alpha shares many of the proinflammatory activities of IL-1. In preliminary studies, especially in patients with Crohn's disease, the effects of the administration of antibodies to TNA-alpha were excellent.
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PMID:Selective immunomodulation in patients with inflammatory bowel disease--future therapy or reality? 881 2

Despite improvements in immunosuppression, rejection occurs in 50% of liver transplant patients and may cause significant morbidity. The most frequent cause of death after liver transplantation is severe infection. Determination of the cytokine network may lead to earlier detection of patients at risk for severe rejection and infection. For this purpose, 81 patients with 85 liver transplants were monitored for cytokines and neopterin on a daily basis. During the first postoperative month, 28 patients (34.6%) developed acute rejection; 14 patients were successfully treated with methylprednisolone (steroid-sensitive rejection), while 14 patients required additional treatment with FK506 and OKT3 (steroid-resistant rejection). Ten patients developed severe infections, and 11 patients experienced asymptomatic cholangitis. Patients with an uneventful postoperative course (n=37) were the control group. One-year patient survival was 88.9%: 1 patient died because of chronic rejection and Pseudomonas urosepsis; a further 4 patients died of aspergillus pneumonia and bacterial sepsis. Soluble TNF-RII, sIL-2R-, and IL-10 levels were significantly elevated 3 days prior to or at the onset of acute steroid-resistant rejection (P < or = 0.01 versus steroid-sensitive rejection and on uneventful postoperative course). An increase in IL-8, neopterin, and sTNF-RII was indicative of severe infection 3 days prior to onset of infection. In this group of patients, a simultaneous increase in IL-10 indicated a lethal outcome of severe infection. During the second week of acute steroid-resistant rejection and lethal infection, a significant rise in IL-1beta, IFN-gamma, and IL-6 was observed (P < or = 0.01 versus control groups). The different patterns in neopterin- and cytokine-increase could differentiate between severe rejection and severe infection. Furthermore, the increase in these parameters indicated severe rejection--i.e., steroid resistance at the onset of acute rejection--which could prompt us to initiate rescue therapy immediately. The ability to detect patients at risk for severe or lethal infection may result in intensified infectious screening and more aggressive antiinfectious treatment. Therefore, routine monitoring of these parameters may lead to changes in therapeutic management of severe acute rejection and infection after liver transplantation.
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PMID:Cytokine pattern during rejection and infection after liver transplantation--improvements in postoperative monitoring? 895 70

Intestinal epithelial cells produce various inflammatory mediators. However, the way in which immunosuppressive agents influence the production of these mediators by intestinal epithelial cells is not understood. The effects of cyclosporine A (CsA), tacrolimus (FK506), and dexamethasone (DEX) on cytokine-induced production of interleukin (IL)-8 in a human colonic cancer cell line (HT-29) were examined. HT-29 cells were stimulated with either IL-1 beta or tumor necrosis factor alpha (TNF alpha) together with CsA, FK506, or DEX. The presence of IL-8 protein was detected by enzyme-linked immunosorbent assay, and the expression of IL-8 messenger RNA (mRNA) by reversetranscription polymerase chain reaction. CsA (1, 5, and 10ng/ml) significantly reduced IL-1 beta-induced IL-8 production (by 32%, 41%, and 48%, respectively), and reduced TNF alpha-induced IL-8 production (by 21%, 42%, and 50%, respectively). FK506 or DEX had no effect on IL-1 beta- or TNF alpha-induced IL-8 production. The expression of IL-8 mRNA was also inhibited by CsA. These findings suggest that CsA may influence the production of inflammatory mediators in colonic cells in a different manner from FK506 and DEX.
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PMID:Cyclosporine A inhibits interleukin-8 production in a human colon epithelial cell line (HT-29). 934 85

FK506, a potent immunosuppressant, has attracted attention for its potential effectiveness in allergic diseases. Although eosinophils are believed to be one of the important effector cells at the site of allergic inflammation, there have been few reports about the direct effect of FK506 on eosinophils. In the present study, we evaluated if FK506 had any effect on the production of IL-8, one of the important chemokines for a variety of inflammatory cells, from human peripheral eosinophils. Purified eosinophils constitutively released IL-8, which was increased with calcium ionophore (10(-6) M). FK506 showed a dose-dependent suppressive effect on IL-8 production by eosinophils stimulated with calcium ionophore, but showed no effect on unstimulated cells. Evaluation of IL-8 mRNA levels by reverse transcription and polymerase chain reaction demonstrated that FK506 suppressed IL-8 gene expression only in activated eosinophils. FK506 further showed a suppressive effect on eotaxin and MCP-1 release from eosinophils. These findings suggested that FK506 might prevent infiltration of inflammatory cells such as eosinophils by, at least in part, inhibiting chemokine release from eosinophils.
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PMID:A potent immunosuppressant FK506 inhibits IL-8 expression in human eosinophils. 1032 81

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.
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PMID:3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator. 1095 6

Interleukin (IL)-8 produced from glioblastoma is suggested to contribute to its own proliferation and progression. Since various external stimuli have been shown to increase intracellular Ca(2+) in glioma cells, we investigated Ca(2+) mobilization-dependent IL-8 expression and effect of cyclosporin A (CsA), an inhibitor of calcineurin (Cn), on the expression and invasive potential of human glioblastoma U251MG cells. Combined treatment with Ca(2+)-ionophore and phorbol-myristate-acetate (A23187/PMA) increased IL-8 mRNA and protein levels. This increase was suppressed by CsA and by another Cn inhibitor FK506. Luciferase reporter gene assay and electrophoretic mobility shift assay revealed that activation of p65-containing nuclear factor-kappaB was essential for A23187/PMA-dependent activation of IL-8 promoter. CsA suppressed the promoter activity by attenuating IkappaB-alpha degradation. U251MG cells expressed IL-8 receptors CXCR-1 and -2, and Matrigel invasion assay revealed that CsA attenuated A23187/PMA-dependent stimulation of invasive potential, probably by inhibiting IL-8 production. In addition, IL-8-dependent proliferation was also suppressed by CsA. Taken together, these results demonstrate the novel inhibitory effects of CsA on glioblastoma cell functions, suggesting CsA as a potential therapeutic adjuvant for glioma treatment.
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PMID:Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells. 1528 17


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