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)

Activation of T cells through the antigen-specific T-cell receptor in combination with a costimulatory signal results in efficient cytokine gene transcription. The CD28-induced signal represents a major costimulatory signal for T cells. A CD28 response element, named CD28RE, was first identified in the interleukin-2 (IL-2) promoter region. Here we demonstrate that the NF-kappaB sequence in the IL-6 promoter functions as a CD28 response element. Mutations in this sequence rendered the IL-6 promoter unresponsive to CD28 costimulation. Moreover, this element could replace the IL-2 CD28RE in conferring CD28 responsiveness to the IL-2 promoter. In analogy to the known CD28 response elements IL-2 CD28RE, IL-8 CD28RE, and the human immunodeficiency virus-1 (HIV-1) NF-kappaB motif, the IL-6 NF-kappaB motif efficiently bound c-Rel, c-Rel/NFKB1, and the recently identified inducible T-cell factor NF-MATp35. However, the IL-6 NF-kappaB sequence together with the IL-8 CD28RE and HIV-1 NF-kappaB sequence differed from the IL-2 CD28RE in the binding of NF-kappaB/Rel family proteins. Although the IL-2 CD28RE exerted selective binding with c-Rel and c-Rel/NFKB1, the other CD28REs allowed efficient binding of a wide range of NF-kappaB/Rel family proteins. The difference in binding specificity correlated with the capacity of the distinct CD28 response elements to function in the context of the IL-6 promoter in response to T-cell activation. Domain swapping experiments revealed that the IL-8 CD28RE and HIV-1 NF-kappaB motif conferred similar responsiveness as the genuine IL-6 NF-kappaB motif in the transcriptional activation of the IL-6 promoter upon CD28 costimulation. In contrast, replacement of the IL-6 NF-kappaB sequence by the IL-2 CD28RE motif strongly reduced the responsiveness of the IL-6 promoter. These data indicate that despite the sequence similarity, two different classes of CD28 responsive elements exist that differ in their NF-kappaB binding capacity and the ability to confer CD28 costimulatory responsiveness toward a heterologous promoter.
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PMID:Functional disparity of distinct CD28 response elements toward mitogenic responses. 1056 14

Nucleic acid immunization has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. Moreover, immune responses induced by DNA immunization can be enhanced by the use of molecular adjuvants. For example, coadministration of costimulatory molecules (CD80 and CD86), proinflammatory cytokines (interleukin-1alpha [IL-1alpha], tumor necrosis factor-alpha [TNF-alpha, and TNF-beta), Th1 cytokines (interleukin-2 [IL-2], IL-12, IL-15, and IL-18), Th2 cytokines (IL-4, IL-5, and IL-10), and granulocytes-macrophage colony-stimulating factor (GM-CSF) with DNA vaccine constructs leads to modulation of the magnitude and direction (humoral or cellular) of the immune responses. To further engineer the immune response in vivo, we compared the induction and regulation of immune responses from the codelivery of chemokine (IL-8, interferon-gamma-inducible protein-10 [gammaIP-10], macrophage inhibitory protein-1alpha [MIP-1alpha], and RANTES) genes with codelivery of cytokine genes. We found that as in cytokine gene codelivery, coimmunization with chemokine genes along with DNA immunogen constructs can modulate the direction and magnitude of induced immune responses. We observed that coimmunization with IL-8, gammaIP-10, and MIP-1alpha genes increased the antibody response. We also found that coinjection with IL-8, gammaIP-10, and RANTES resulted in a dramatic enhancement of T helper (Th) proliferation response. Furthermore, among all coinjection combinations, we found that RANTES coinjection caused a high level of cytotoxic lymphocyte (CTL) enhancement. This enhancement of CTL responses observed from the coinjection with RANTES was CD8+ T cell dependent. Together with earlier reports on the utility of coimmunizing immunologically important molecules with DNA immunogens, we demonstrate the potential of this strategy as an important tool for the development of more rationally designed vaccines.
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PMID:Chemokine gene adjuvants can modulate immune responses induced by DNA vaccines. 1084 Oct 77

Immunotherapy with intravenous recombinant human interleukin-2 (rh IL-2) may be accompanied by hypotension and the emergence of capillary leak syndrome. Nitric oxide (NO) is supposed to be responsible for both side effects. The aim of the current investigation was to elucidate the relationship between pro- and anti-inflammatory cytokines and the production of NO in eight tumor patients receiving intravenous rh IL-2 continuously over a time period of 120 hours. Markers of systemic inflammation, as well as nitrate plasma levels, were consecutively determined. Significant changes in the levels of pro-inflammatory cytokines IL-6 and IL-8 were observed (p < 0.05). In contrast to the anti-inflammatory cytokine IL-10, which did not increase significantly, the serum concentrations of the soluble tumor necrosis factor receptors (sTNFr) I and II rose continuously and significantly during the observation period (p < 0.05). In parallel, a significant rise in nitrate plasma levels was observed (p < 0.05). Moreover, there were highly significant correlations between nitrate and IL-6 serum levels (p < 0.05), nitrate and sTNFr-I (p < 0.05), nitrate and sTNFr-II (p < 0.05), and between IL-6 and IL-10 (p < 0.05), respectively. We conclude that immunotherapy with IL-2 promotes a pro-inflammatory state, parallelled by an increased production of nitric oxide. Although anti-inflammatory responses accompany this process, they are not able to diminish the production of nitric oxide.
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PMID:Relation of pro- and anti-inflammatory cytokines and the production of nitric oxide in patients receiving high-dose immunotherapy with interleukin-2. 1102 23

Conflicting data on the role of interleukin-2 in the recruitment of eosinophil granulocytes (EOS) to sites of inflammation have been presented. The objective of the present study was to investigate the effect of recombinant human IL-2 and anti-IL-2 on the migration of purified blood EOS. Neutralizing antibodies to IL-2 were added to a cytokine mixture with significant eosinophil chemotactic activity (ECA), and afterwards the ECA was tested on EOS from both normal and allergic donors. EOS migration was measured by a modification of the Boyden technique, using a 48-well microchemotaxis chamber. Recombinant human IL-2 was either added to the lower compartment of the chemotaxis chamber, or to the EOS for a pre-incubation period of 20 min, before migration assays towards the chemotaxins were performed. Anti-IL-2 caused a significant increase of EOS migration towards the cytokine mixture. Pre-incubation of the EOS with rhIL-2 inhibited the chemotaxis towards RANTES, PAF, IL-8 and eotaxin, and EOS migration towards IL-2 was lower than that towards buffer. These effects were more pronounced on EOS from normal than from allergic donors. Priming of the EOS with IL-5 prevented the inhibitory effect of IL-2. We hypothesize that IL-2 acts as an autocrine regulator of EOS migration, and that this inhibitory effect may be downregulated in allergy, allowing an increased migration of EOS towards chemotactic factors.
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PMID:Interleukin-2 inhibits eosinophil migration but is counteracted by IL-5 priming. 1125 26

It has long been suspected that pentachlorophenol (PCP) exerts a damaging influence on the immune system. In this study, the possible relationship between blood levels of PCP and immune function was studied in 190 patients who had been exposed for more than 6 mo to PCP-containing pesticides. The patients suffered from frequent respiratory infections and general fatigue. Lymphocyte subpopulations, in-vitro responses to mitogens, allogeneic stimulator cells, plasma neopterin, cytokines, soluble cytokine receptors, soluble adhesion molecules, and immunoglobulin autoantibodies were determined. A dose-response relationship between blood levels of PCP and cellular and humoral immune parameters was established. Blood levels of PCP were associated negatively with (a) total lymphocyte counts (p = .0002), CD4/CD8 ratios (p = .0015), and absolute counts of CD3+ (p < .0001), CD4+ (p < .0001), CD16+ (p < .0001), CD25+ (p = .0003), DR+ (p < .0001), CD8+/56+ (p = .020), and CD19+ cells (p = .092); (b) plasma levels of interleukin-2 (IL-2) (p < .0001), soluble IL-2R (p < .0001), IL-6 (p < .0001), IL-10 (p = .0039), interferon-gamma (IFN-gamma) (p < .0001), tumor necrosis factor-alpha (TNF-alpha) (p < .0001), transforming-growth factor-beta2 (p = .023), soluble IL-1 receptor antagonist (sIL-1 RA) (p < .0001), soluble intercellular adhesion molecule-1 (p = .0003); and (c) immunoglobulin (Ig) M-anti-Fab type autoantibodies (p = .0353). PCP levels were associated positively with (a) number of impaired stimulation assays per patient (p = .041); (b) number of circulating CD11b+ monocytes (p = .0015); and (c) plasma levels of neopterin (p < .0001), IL-4 (p = .020), and sIL-6R (p = .020). Compared with patients who had PCP plasma levels that were less than or equal to 10 microg/l, patients with blood levels of PCP that exceeded 10 microg/l experienced the following more often: low numbers of total blood lymphocytes (p = .054), CD3+ (p = .0014), CD4+ (p = .0001), DR+ (p = .0003), CD16+ (p = .0033), and CD25+ cells (p = .0033). In addition, the same aforementioned patients experienced the following more frequently: undetectable plasma levels of IL-2 (p = .0057), IL-6 (p = .042), IL-8 (p = .038), IL-10 (p = .0001), TNF-alpha (p = .0062), and IFN-gamma (p = .016); and impaired in-vitro responses of lymphocytes (p = .071). The authors concluded that increased blood levels of PCP were associated significantly with cellular and humoral immunodeficiencies. Recurrent respiratory infections and general fatigue could originate from PCP-associated immunosuppression.
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PMID:Association of elevated blood levels of pentachlorophenol (PCP) with cellular and humoral immunodeficiencies. 1125 60

The kinetics of interleukin-2 (IL-2), IL-6, IL-8 and IL-10 gene expression in concanavalin A (Con A)-activated whole blood (WB) and peripheral blood mononuclear cell (PBMC) cultures were examined using reverse transcriptase-polymerase chain reaction (RT-PCR). Unstimulated PBMC or WB cultures failed to show increases in basal cytokine PCR amplicon levels for any cytokine examined. PBMC cultures demonstrated peak expression of IL-2, IL-6, IL-8 and IL-10 mRNA levels at 12, 24, 24 and 6h, respectively. WB cultures exhibited peak IL-2, IL-6, IL-8 and IL-10 mRNA levels at 24, 12, 6 and 24h, respectively. PBMC cultures consistently exhibited higher levels of IL-2 mRNA at all times examined than did WB cultures. WB cultures consistently had higher levels of IL-6 mRNA than PBMC cultures. IL-8 and IL-10 protein levels in PBMC cultures were first detected 12h after stimulation and continued to increase in concentration through 48h. In WB cultures, IL-8 and IL-10 protein levels were first noted at 12 and 6h, respectively. WB culture IL-8 and IL-10 levels quickly reached equilibrium after being detected and remained at levels lower than those noted in PBMC cultures. These results show WB cultures represent an approach with reduced cost and time when compared to traditional cell culture and isolation methods. It may also produce an in vitro test system that more closely resembles in vivo conditions.
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PMID:Differential cytokine mRNA expression in swine whole blood and peripheral blood mononuclear cell cultures. 1135 49

CD28 is the major costimulatory molecule on T cells. CD28 activation, in conjunction with T-cell receptor engagement, up-regulates transcription of several cytokines, including interleukin-2 (IL-2), through transcriptional activation of the RE/AP composite element. Although CD28 is not normally expressed on B cells or plasma cells, more than 90% of extramedullary myelomas (a late stage B-cell neoplasm) express CD28. The functional significance of this is unknown. The results of this study demonstrate that CD28 stimulates transcriptional activation of RE/AP-based reporters in B cells and myeloma cells. However, CD28 stimulation does not up-regulate IL-2 production in myeloma cell lines, demonstrating that the IL-2 promoter may not be a relevant RE/AP-containing target of CD28 in myelomas. Instead, an RE/AP composite element has been identified within the promoter of the IL-8 gene, a chemokine that promotes angiogenesis. Furthermore, stimulation of endogenous CD28 expressed by 3 myeloma cell lines increased IL-8 production. Therefore, the study demonstrates that CD28 is functional in myelomas to up-regulate transcription of endogenous genes, including IL-8. The proposal is made that aberrant expression of CD28 may play a role in the progression of multiple myeloma.
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PMID:Endogenous CD28 expressed on myeloma cells up-regulates interleukin-8 production: implications for multiple myeloma progression. 1141 79

In this study, soluble receptor of interleukin-2, interleukin-8, creatine kinase, and creatine kinase MB isoenzyme levels were determined serially before, during, and after cardiopulmonary bypass in blood samples of 24 patients. Interleukin-2 receptor levels were 683+/-80 U/ml in the preoperative period and 640+/-60 U/ml during hypothermia. Subsequently, these levels increased significantly at the end of the procedure (791+/-70 U/ml, P<0.01), remaining elevated 1 h after (882+/-92 U/ml, P<0.001) and reaching peak values 24 h postoperatively (1,752+/-200 U/ml, P<0.001). Preoperative plasma values of interleukin-8 were 230+/-43 pg/ml. Interleukin-8 concentrations were 185+/-25 pg/ml during hypothermia. The peak interleukin-8 levels were observed at the end of cardiopulmonary bypass (754+/-94 pg/ml, P<0.001) and tended to decrease 1 h after the procedure (643+/-76 pg/ml, P<0.001), declining to preoperative values, 24 h postoperatively (273+/-41 pg/ml). Interleukin-2 receptor levels correlated well with creatine kinase levels during the procedure. Furthermore, creatine kinase MB levels were correlated with interleukin-2 receptor values only at the end and 1 h after completion of cardiopulmonary bypass. We concluded that interleukin-8 and Interleukin-2 receptor levels are elevated after cardiopulmonary bypass and may contribute to myocardial injury as reflected by increased levels of creatine kinase and creatine kinase MB and correlations between interleukin-2 receptor and both creatine kinase and creatine kinase MB levels.
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PMID:Soluble interleukin-2 receptor and interleukin-8 plasma levels during and after cardiopulmonary bypass: correlations with creatine kinase and creatine kinase MB. 1146 97

Immunotherapy with interferon-alpha (IFNalpha) may induce depressive symptoms, anxiety and major depression when administered for at least 1-3 months at a dose of 3-10 MUI daily, twice or three times a week. Previously, it has been shown that immunotherapy with interleukin-2 (IL-2) significantly induces the cytokine network, as measured by increases in serum IL-6, IL-10 and the IL-2 receptor (IL-2R), and that the immunotherapy-induced changes in the cytokine network are significantly correlated with the increases in depression ratings. The main aim of this study was to examine the effects of immunotherapy with IFNalpha on the cytokine network in relation to changes in depression and anxiety ratings. Fourteen patients, affected by chronic active C-hepatitis, were treated with IFNalpha (3-6 MUI s.c. three/six times a week for 6 months) and had measurements of serum IFN-gamma (IFNgamma), IL-2, IL-6, IL-6R, IL-8 and IL-10 before starting therapy and 2, 4, 16 and 24 weeks after immunotherapy with IFNalpha. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A), respectively. Repeated measure (RM) design ANOVAs showed significantly higher MADRS and HAM-A scores 2-4 weeks and 4-6 months after starting IFNalpha-based immunotherapy than at baseline. RM design ANOVAs showed significantly higher serum IL-6 and IL-8 levels 2-4 weeks after starting IFNalpha-based immunotherapy and higher serum IL-10 levels 2-4 weeks and 4-6 months after starting therapy than at baseline. There were significant relationships between the IFNalpha-induced changes in serum IL-6 or IL-8 and the depression and anxiety scores. The findings show that IFNalpha-based immunotherapy induces the cytokine network and that IFNalpha-induced increases in IL-6 predicts the development of depressive symptoms. Depressive symptoms following IFNalpha treatment may be secondary to cytokine induction, including that of IL-6.
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PMID:Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. 1174 Sep 74

Cytokines and soluble cellular receptors are involved in inflammatory processes and probably in the pathogenesis of parasite and bacterial diseases. In a previous study, we reported increased levels of soluble receptors of interleukin-2 (sIL2-R) in children with acute Chagas' disease, one of the main parasitic infections that is endemic in Latin America. We sought to analyze the pattern of different cytokines and soluble receptors in the sera of children with chagasic infection. Children with acute and indeterminate stages of Chagas' disease, as well as nonchagasic children, were studied. Sera were assayed by enzyme-linked immunosorbent assay to measure the levels of tumor necrosis factor alpha (TNF-alpha), IL-6, IL-2, IL-8, IL-12, sIL-2R, and the soluble receptors of CD8 and CD4 (sCD8 and sCD4). sIL-2R and sCD8 showed the highest levels in serum in acutely infected children, decreasing after specific antiparasite therapy. Chronic children showed a pattern similar to the one of nonchagasic children. Although they were not statistically significant, TNF-alpha, IL-6, and sCD4 showed a tendency to reach high levels in the acutely infected group, whereas IL-2, IL-8, and IL-12 did not reveal changes with respect to the noninfected children. In summary, we report here the patterns of cytokines and soluble receptors in in the sera of children infected with Trypanosoma cruzi; we found significantly increased levels of sIL-2R and sCD8 in acute infection that decreased after therapy, and high levels of TNF-alpha, IL-6, and sCD4 in some of the acute patients. The measurement of sIL-2R and sCD8 may provide a useful tool in the follow-up of children with Chagas' disease.
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PMID:Patterns of cytokines and soluble cellular receptors in the sera of children with acute chagas' disease. 1241 68


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