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 effect of inflammatory mediators on the expression of several surface adhesion molecules on the human mast-cell line (HMC)-1 was studied. By flow cytometry, it could be shown that among several surface adhesion molecules (ICAM-1/CD54, VLA-4/CD49d, Mac-1/CD11b, LFA-1/CD11a, LFA-2/CD2, LFA-3/CD58, VCAM-1), only the constitutively expressed immunoglobulin family member intercellular adhesion molecule-1 (ICAM-1) is modulated by proinflammatory cytokines on HMC-1 mast cells. Stimulation with tumor necrosis factor-a (TNF-alpha) and interferon-gamma (IFN-gamma) resulted, in addition to interleukin-(IL-)4, in selective upregulation of ICAM-1 expression. Costimulation of either IL-4 or IFN-gamma with TNF-alpha further increased the ICAM-1 expression as compared to the stimuli alone. In contrast, stem-cell factor (SCF), granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-10, IL-8, monocyte chemotactic and activating factor (MCAF), and the complement split product C5a failed to modulate the expression of any adhesion molecule examined. The levels of cytoplasmic free calcium in HMC-1 mast cells were not altered by cross-linking surface ICAM-1, suggesting linkage of other intracellular signaling pathways. This cytokine-induced upregulation of ICAM-1 expression might reveal a putative regulatory mechanism of mast-cell interaction with effector cells bearing the counterparts of ICAM-1 (CD54), the molecules Mac-1 (CD11b/CD18) and leukosialin (CD43), and the principal ligand LFA-1 (CD11a/CD18).
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PMID:Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on the human mast-cell line (HMC)-1 by inflammatory mediators. 890 94

In renal transplant, patients, the number of T cells expressing high levels of LFA-1 (LFA-1-bright) and of T cells expressing CD57 increases in response to viral infection, even if the latter is asymptomatic. Their role in long-term renal transplant patients with cytomegalovirus (CMV) antigenemia and concomitant transplant dysfunction was investigated. For this purpose, this study used triple-color flow cytometry, fluorescence-activated cell sorting of peripheral blood T cells (CD3+/LFA-1-dim or -bright and CD8+/CD57+ or CD57- subsets), and subsequent semiquantitative reverse transcription-polymerase chain reaction. Cytokine mRNA levels for interleukin (IL)-1 beta, IL-2, IL-4, IL-8, IL-10, tumor necrosis factor alpha, and interferon-gamma, as well as Granzyme A and IL-2R p55 and p75 transcripts were determined and compared in peripheral blood mononuclear cells and in separated T cell subsets. Although in patients with CMV infection and/or rejection, cytokine transcripts were readily detected and the levels in the CD3+/LFA-1-bright subsets were, by orders of magnitudes, higher than in the LFA-1-dim subset, hardly any cytokine message was found in patients without CMV infection or rejection episodes or in control subjects. The expression of Granzyme A, which is involved in cytotoxic T lymphocyte-mediated cytotoxicity, was not upregulated in LFA-1-bright T cells, which is in discordance with cytokine levels. Differences between CD57+ and CD57- T cells were limited to the IL-2R p55 mRNA, of which the former expressed significantly less than the latter. It is concluded that upon virus-induced activation of peripheral blood T cells, an effector type that is marked by high inflammatory but small cytotoxic potential is produced. The results of this study propose that these cells represent a correlate of persistent immune activation and are liable to produce graft dysfunction, although they are unable to clear the organism from virus infection because of their lack of cytotoxic potential.
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PMID:Peripheral T cell activation in long-term renal transplant patients: concordant upregulation of adhesion molecules and cytokine gene transcription. 895 42

Neutrophil emigration through endothelial cells under shear flow involves several adhesion processes including cell rolling, arrest, and transmigration. Rolling is mediated by selectins, while arrest and transmigration both require activated CD18 integrins. One mode of CD18 activation is via selectins expressed on neutrophils and endothelial cells. We have recently reported that cross-linking of L-selectin (CD62L) resulted in the rapid activation of CD18-dependent adhesion. In the current study, we examine whether binding of E-selectin (CD62E) and L-selectin can activate neutrophil CD18-dependent adhesion under shear flow. Human ICAM-1 (CD54) and E-selectin were co-transfected into L cells. Neutrophil capture, rolling, and arrest on these monolayers were quantitated in a parallel plate flow chamber at a wall shear stress of 2.0 dyne/cm2. Under these conditions, E-selectin supported cell capture and rolling on the monolayer, but did not trigger CD18-mediated cell arrest within 200 microm of rolling. However, when neutrophils were treated with anti-L-selectin mAb and cross-linked with a secondary mAb, approximately 50% of the cells arrested within 54 microm. Cell arrest was also observed in response to IL-8 stimulation. A subthreshold level of IL-8 in combination with L-selectin cross-linking potentiated the level of cell arrest due to either stimulus alone. The transition to cell arrest involved both LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18). Blocking either subunit alone failed to reduce arrest, while blocking both molecules with mAbs reduced the number to baseline levels. These data support the conclusion that L-selectin, but not E-selectin, can signal the transition from neutrophil rolling to cell arrest under shear flow.
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PMID:Neutrophil CD18-dependent arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow can be activated through L-selectin. 897 12

Tumor necrosis factor-alpha occupies a central role in rheumatoid arthritis (RA) pathogenesis. We now report that interleukin-15 (IL-15) can induce TNF-alpha production in RA through activation of synovial T cells. Peripheral blood (PB) T cells activated by IL-15 induced significant TNF-alpha production by macrophages via a cell-contact-dependent mechanism. Freshly isolated RA synovial T cells possessed similar capability, and in vitro, IL-15 was necessary to maintain this activity. IL-15 also induced direct TNF-alpha production by synovial T cells. In contrast, IL-2 induced significantly lower TNF-alpha production in either cell-contact-dependent or direct culture, and IL-8 and MIP-1 alpha were ineffective. Antibodies against CD69, LFA-1 or ICAM-1 significantly inhibited the ability of T cells to activate macrophages by cell contact.
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PMID:Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. 962 50

The expression and up-regulation of cell adhesion molecules on a human colonic epithelial cell line HT-29, and the peripheral blood T lymphocyte proliferation responses to bacterial superantigens presented by this cell line were investigated, compared with peripheral blood monocytes. In HT-29 cells, there was constitutive expression of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-3 (LFA-3) at a low level, but no constitutive expression of HLA-DR, LFA-1, B7-1 and B7-2 molecules. After stimulation with the supernatants of staphylococcal enterotoxin B (SEB)-stimulated peripheral blood mononuclear cells for 48 h, there was significant up-regulation of HLA-DR and ICAM-1 molecules (both > 90% positive). However, this stimulation had no effect on the expression of LFA-1, B7-1, B7-2 and LFA-3 molecules. In the presence of all tested superantigens SEB, toxic shock syndrome toxin-1, and streptococcal pyogenic exotoxin A, stimulated HT-29 cells caused significant T cell proliferation. When monocytes were used as antigen-presenting cells (APC), the MoAbs against HLA-DR, B7-2 and LFA-3 showed a significant inhibition of SEB-induced T cell proliferation. Anti-ICAM-1 MoAb had no effect on this response. On the other hand, when stimulated HT-29 cells were used as APC, the MoAbs against HLA-DR and ICAM-1 significantly inhibited SEB-induced T cell proliferation. In contrast to monocytes, anti-B7-2 and anti-LFA-3 had no effect on this response. SEB could not induce HT-29 cells to produce IL-8 directly; however, SEB significantly induced the stimulated HT-29 cells to produce IL-8 in the presence of T cells. Thus these data demonstrate that the products of superantigen-stimulated T cell activation can increase the expression of HLA-DR and ICAM-1 molecules on HT-29 cells significantly. Stimulated HT-29 cells can serve as APC to bacterial superantigens. This response is an HLA-DR- and ICAM-1-dependent, but B7-2- and LFA-3-independent process, which was different from professional APC monocytes.
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PMID:Accessory cell function of a human colonic epithelial cell line HT-29 for bacterial superantigens. 918 80

The expression of intercellular adhesion molecule-1 (CD54 or ICAM-1) on epithelial cells during acute or chronic inflammation may favor the interaction between epithelial cells and leukocytes expressing the natural ligands of ICAM-1, LFA-1 (CD11a/CD18), and Mac-1 (CD11b/CD18). We have evaluated in vitro the expression of ICAM-1 by a conjunctival (WK) and an intestinal (I407) human continuous epithelial cell line. Cells were cultured for 24 h in the presence or absence of IFN-gamma, TNF-alpha, IL-1 beta, IL-4, IL-6, IL-8, IL-10, and TGF-beta 1. Both epithelial cell lines showed a constitutive expression of ICAM-1. IFN-gamma at 500 U/ml and TNF-alpha at 200 ng/ml upregulated ICAM-1 expression; IL-1 beta at 100 pg/ml upregulated ICAM-1 on WK cells only. Cells cultured in the presence of both IFN-gamma and TNF-alpha exhibited a mean fluorescence intensity far greater than those cultured with IFN-gamma or TNF-alpha alone. I407 and WK cells were able to release soluble ICAM-1. IFN-gamma and TNF-alpha enhanced the release of sICAM-1. IL-4, IL-6, IL-8, IL-10, and TGF-beta 1 did not affect either ICAM-1 expression or sICAM-1 release. In conclusion, continuously cultured human epithelial cells may express ICAM-1 on their surface and release it in culture medium. These phenomena are upregulated by proinflammatory cytokines.
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PMID:Intercellular adhesion molecule-1 on cultured human epithelial cell lines: influence of proinflammatory cytokines. 920 63

Dysfunction of cytokine secretion pattern has been suggested to play a central role in the immunopathogenesis of HIV infection. In fact a shift of T helper cell functions from a Th1-type to TH0- or TH2-type has been observed in HIV-1 infected subjects undergoing disease progression. The inhalance of cytokine network is accompanied by persistent activation of the immune system, impaired ability to mount a proper activation response (anergy), and priming to apoptosis. Extensive investigation during the last decade has been conducted on the influence of HIV-1 gp120 or of its precursor gp160 on several lymphocyte and monocyte functions. Gp120 is able to rise intracellular calcium concentration and to induce the formation of inositol triphosphate, can block mitogen- or antigen-driven T cell activation, can induce altered cytokine production by activated PBMC subpopulations, determines impaired cytotoxicity and chemotactic response to antigens, interferes with the activity of antigen presenting cells, enhances or induces apoptosis, stimulates polyclonal B cell activation and induces or up-modulates a number of cytokines, including IL-6. TNF, IL-1-alpha and -beta, IL-10 and IL-8. Furthermore, both IFN-alpha and -gamma, as well as several markers of IFN activity, such as beta 2-microglobulin and neopterin, are induced in gp120-stimulated PBMC. However, neither IL-4 (Th2-type) nor IL-2 (Th1-type), nor DNA synthesis are activated by gp120. On the other hand gp120-stimulated PBMC express increased IL-2 receptors, and can be induced by exogenous IL-2 to proliferate, suggesting that they are in a state of at least partial activation. According to this hypothesis, other activation markers, both early (such as CD69), and late (such as CD45RO and CD71), are induced by gp120, but this even partial activation does not lead to the ability of PBMC to support productive infection by HIV-1, unless in the presence of exogenous IL-2. The HIV-induced cytokines can influence HIV infection either directly, by up- or down-modulating virus replication, or indirectly, by modulating the expression of cellular molecules. In fact, during the budding process, the HIV envelope captures a number of cell membrane proteins, including cytokine receptors such as IL-2R, adhesion molecules such as LFA-1, ICAM-1, -2, HLA Class I and II, as well as cell lineage markers. Gp120-induced cytokines, particularly IFN-gamma, upmodulate the cellular expression of intercellular adhesion molecules, such as ICAM-1. We have shown that the IFN-gamma-driven increase of the expression of ICAM-1 by cells chronically infected with HIV-1 can be transmitted to the virus progeny, resulting in phenotypic alteration of the virus, and leading to the expansion of its host cell spectrum to CD4-negative cells expressing the appropriate ligands, i.e. LFA-1. Intercellular adhesion molecules are also involved in the cell-mediated transmission of HIV infection, and the increased ICAM-1 expression induced by IFN-gamma determines a stimulation of the transmission of HIV from abortively infected endothelial cells to permissive CD4 lymphocytes. On the whole, these data indicate that HIV, or its soluble products such as gp120, can modify several PBMC functions, by inducing a number of cytokines and a partial state of immune activation. It is possible that the gp120-driven changes of PBMC functions are not only an epiphenomenon of HIV infection, but rather, it is likely that they can participate in the immunopathological events responsible for disease progression.
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PMID:Induction of lymphomonocyte activation by HIV-1 glycoprotein gp120. Possible role in AIDS pathogenesis. 960 76

Neutrophils, or polymorphonuclear leukocytes (PMNLs), migrate through vascular endothelium and in connective tissue during inflammation. In rats with adjuvant arthritis, migration to joints of radiolabeled (111In) blood PMNLs was examined to define the role of specific selectin and integrin adhesion molecules in this process. Based on monoclonal antibody studies, P-selectin was required for normal PMNL migration to the joints. Although E-selectin alone was not essential, it mediated PMNL accumulation when the P-selectin mechanism was blocked. However, 30% to 40% of the PMNL accumulation was L-, P-, and E-selectin-independent. The integrins, LFA-1 and Mac-1 (CD11/CD18), and VLA-4 mediated PMNL migration to arthritic joints. However, 20% to 40% of PMNL accumulation was via CD18- and VLA-4-independent mechanisms. Human PMNL migration in vitro across unstimulated human umbilical vein endothelial cells (HUVEC), induced by C5a or IL-8, was virtually all mediated by the CD18 (beta2) integrins, LFA-1 and Mac-1. PMNL transendothelial migration was partly CD18-independent (35%) when endothelium was activated with cytokines, such as interleukin-1, and a chemotactic gradient, such as C5a, was also present. This CD18-independent migration was partially E-selectin-dependent in vitro. PMNL migration across synovial fibroblasts induced by C5a was mediated by Mac-1, VLA-4, VLA-5, and VLA-6, functioning in concert. However, up to 30% of migration was via mechanisms as yet to be defined. Thus, PMNL transendothelial and extravascular migration involves some shared, and some distinct mechanisms, as well as some yet to be identified. Defining these mechanisms may help develop therapies for controlling PMNL involvement in inflammation in the vascular and extravascular spaces.
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PMID:Adhesion molecules mediating neutrophil migration to arthritis in vivo and across endothelium and connective tissue barriers in vitro. 983 14

We evaluated the relative contribution of ICAM-1 and ICAM-2, known ligands on endothelium for LFA-1 and Mac-1, in spontaneous neutrophil (PMN) transendothelial migration (TEM) across IL-1-activated HUVEC monolayers or TEM induced by C5a or IL-8 across unstimulated HUVEC grown on polycarbonate filters. Adhesion blocking mAb to ICAM-1 [R6.5 F(ab)2] or ICAM-2 [CBR IC2/2 F(ab)2] tended to inhibit TEM under each condition but, in general, inhibition was significant only with both ICAM-1 and ICAM-2 blockade. mAb to LFA-1 partially inhibited migration to C5a or IL-8 across unstimulated HUVEC and inhibition was not altered by additional treatment of HUVEC with mAbs to ICAM-1 and -2. In contrast, with IL-1 HUVEC, mAb to ICAM-1 significantly inhibited this LFA-1-independent TEM. mAb to Mac-1 alone partially inhibited TEM and, when combined with mAb to LFA-1, migration was almost completely blocked with all TEM conditions tested. The contribution of alternate ligands for Mac-1 in mediating Mac-1-dependent but ICAM-1/-2-independent C5a-induced TEM was examined using anti-LFA-1-treated PMN and anti-ICAM-treated resting HUVEC. Addition of RGD peptides, fibronectin, fibrinogen, heparins, collagens alone or in combination, even to heparinase-treated HUVEC, did not inhibit this Mac-1-mediated PMN TEM. The results indicate that: (1) LFA-1 mediates PMN TEM primarily by interaction with ICAM-1 and ICAM-2; (2) ICAM-2 may function in concert with ICAM-1 in this role, especially on unstimulated endothelium, and (3) Mac-1 on PMN also plays a major role in TEM and can utilize yet to be identified ligands distinct from ICAM-1 or -2, especially on unstimulated endothelium.
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PMID:Role of ICAM-1 and ICAM-2 and alternate CD11/CD18 ligands in neutrophil transendothelial migration. 988 54

Crohn's disease (CD) lesions are characterized by a marked neutrophilic infiltrate associated with enhanced mucosal IL-8, contrasting with low serum IL-8 levels. The aim of this study was to investigate the effects of circulating GROalpha and IL-8 on neutrophil priming and migration. The expression of surface molecules involved in rolling (CD62L, CD15) and firm adhesion (Mac-1 and LFA-1) to endothelial cells was assessed by flow cytometry, while the chemotactic response of PMN to IL-8 and to fMLP was investigated in a Boyden chamber assay. In addition, IL-8 and GROalpha levels were determined by ELISA in plasma samples and in culture supernatants of purified polymorphonuclear neutrophils (PMN) and peripheral blood mononuclear cells (PBMC) from patients with CD and healthy blood donors. This study revealed an upregulation of CD11b (Mac-1) membrane expression on circulating PMN from patients with CD, as assessed by the mean fluorescence intensity which reflects antigen density. Furthermore, an enhanced chemotactic response towards both fMLP and IL-8 of PMN from CD patients was observed. Despite often undetectable levels of circulating IL-8, all plasma samples were positive for GROalpha, with a significant increase in CD patients when compared to donors. In vitro, equivalent concentrations of GROalpha were able to increase the IL-8 driven chemotaxis of PMN. In conclusion, blood PMN from patients with CD showed an enhanced capacity to be recruited into inflammed intestinal mucosa, which could be due to an increased expression of CD11b (Mac-1) as well as an increased chemotactic response toward fMLP or IL-8. This priming effect of PMN in CD may partly occur through elevated circulating GROalpha levels.
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PMID:Circulating growth-regulator oncogene alpha contributes to neutrophil priming and interleukin-8-directed mucosal recruitment into chronic lesions of patients with Crohn's disease. 988 9


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