Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Inflammatory cells infiltrate the liver in response to microbial infection or hepatic injury. To assess the potential role hepatocytes may play in initiating or amplifying the acute inflammatory response in the liver, we used three human hepatocyte cell lines and primary human hepatocyte cultures to characterize the repertoire of cytokines that can be expressed and regulated in hepatocytes in response to agonist stimulation or bacterial infection. As reported herein, a proinflammatory cytokine gene program that includes C-X-C and C-C chemokines [interleukin-8(IL-8), growth related (GRO)-alpha, GRO-beta, GRO-gamma, epithelial neutrophil activating peptide-78 (ENA-78), and RANTES] and the cytokines tumor necrosis factor-alpha (TNF-alpha) and macrophage colony stimulating factor was upregulated in human hepatocytes after stimulation with IL-1 alpha or TNF-alpha or bacterial invasion. In contrast, expression of hematopoietic/ lymphoid growth factors by the same cells was either down-regulated (erythropoietin and stem cell factor) or unchanged (IL-7 and IL-15) in response to the identical stimuli. Hepatocytes did not express cytokines that often are associated with the regulation of antigen-specific immune responses (IL-2, IL-4, IL-5, IL-10, IL-12p40, IL-13, and interferon-gamma) or genes for several other proinflammatory cytokines [IL-1 alpha, IL-6, monocyte chemotactic protein-1 (MCP-1), and MCP-3] or hematopoietic growth factors (granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, IL-3, and IL-11). Together, these studies suggest that hepatocytes can both initiate and amplify acute inflammatory responses in the liver through the regulated expression and secretion of a specific array of proinflammatory cytokines.
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PMID:Human hepatocytes express an array of proinflammatory cytokines after agonist stimulation or bacterial invasion. 927 10

Recently, we have established a method for the culture of human spleen slices in vitro. The procedure allows thin slices (200-350 microns) of human spleen to be cultured for up to 7 days. Using this method, we have previously established that unstimulated spleen slices spontaneously synthesize and secrete considerably higher levels of immunoglobulin than suspension cultures of the same tissue run in parallel. In this study, we report that there are also marked differences in the cytokine secretion profile between slices and suspensions and in their proliferative response. In brief, control and PHA-stimulated spleen slices secrete high levels of IL-1 beta, IL-6, IL-8 and IL-11 while the levels found in suspension supernatants are appreciably lower. By way of contrast, high levels of IL-2, IL-4, IL-10 and TNF alpha are found in suspension culture supernatants following PHA stimulation while the response in slice cultures is extremely low. These differences are also reflected in the results obtained at the cellular (intracellular cytokine) level. Additional studies reveal that spontaneous immunoglobulin production observed in spleen slices can be inhibited by the addition of specific antibodies to IL-1 beta, IL-6 and TNF alpha and that the bulk of the IL-6 and IL-1 beta detected in culture supernatants represents de novo synthesis. Finally, the background and mitogen-stimulated proliferative response of tissue slices is meagre compared with that observed in spleen suspensions suggesting that proliferation in the former is held under strict control. Collectively, we believe that the tissue slice procedure described provides us with a system for studying integrated events in lymphoid tissues in vitro and evaluating immunomodulatory substances of potential clinical importance.
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PMID:Organ culture of human lymphoid tissue. II. Marked differences in cytokine production and proliferation between slice and suspension cultures of human spleen. 929 92

Activin A is a cytokine whose multiple functions have yet to be fully determined. In this study, the role of proinflammatory cytokines in regulatory control of activin A production was shown in synoviocytes and chondrocytes. Additional facets of functional inflammation-related activities of activin A were also determined. Results showed that activin A concentrations in the synovial fluid of patients with rheumatoid arthritis and gout were elevated relative to those in patients with osteoarthritis. Further studies showed that production of activin A by synoviocytes and chondrocytes in culture was stimulated by cytokines such as IL-1, transforming growth factor-beta (TGF-beta), interferon-gamma (IFN-gamma), and IL-8, consistent with previous studies in regard to the control of activin A production in marrow stromal cells and monocytes by cytokines, glucocorticoids and retinoic acid. In addition, the relationship of activin A to IL-6-induced biological activities was investigated. Three major IL-6 activities involved in inflammatory responses were found to be suppressed by activin A. In a dose-dependent manner, activin A efficiently suppressed IL-6-induced proliferation of 7TD1 B lymphoid cells, phagocytic activity of monocytic M1 cells, and fibrinogen production in HepG2. Therefore, it is likely that activin A serves as a suppressor for IL-6, dampening inflammatory responses, and has the potential to perform some previously unrecognized roles in inflammation.
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PMID:Suppression of IL-6 biological activities by activin A and implications for inflammatory arthropathies. 956

Leukocyte adhesion to endothelium and extravasation are dynamic processes that require activation of integrins. Chemoattractants such as IL-8 and FMLP are potent activators of leukocyte integrins. To compare the chemoattractant-stimulated activation of three integrins, alpha 4 beta 7, alpha L beta 2, and alpha V beta 3, in the same cellular context, we expressed an IL-8 receptor (IL-8RA) and FMLP receptor (FPR) in the lymphoid cell line JY. Chemoattractants induced a rapid increase in alpha L beta 2- and alpha V beta 3-dependent JY adhesion within 5 min, and it was sustained for 30 min. In contrast, stimulation of alpha 4 beta 7-dependent adhesion was transient, returning to basal levels by 30 min. The activation profiles of the integrins were similar regardless of whether IL-8 or FMLP was used for induction. We also demonstrate that alpha 4 beta 7-dependent adhesion was uniquely responsive to the F actin-disrupting agent cytochalasin D and the protein kinase C (PKC) inhibitor chelerythrin. While alpha V beta 3- and alpha L beta 2-mediated cell adhesion was significantly reduced by cytochalasin D, alpha 4 beta 7-mediated adhesion was enhanced. Chelerythrin inhibited both the IL-8 and PMA activation of alpha L beta 2 and alpha V beta 3. In contrast, inducible alpha 4 beta 7 activity was unaffected, and basal activity was increased. These findings demonstrate that the mechanism of alpha 4 beta 7 regulation by chemoattractants is different from that of alpha L beta 2 and alpha V beta 3 and that it appears to involve distinct cytoskeletal and PKC dependencies. In addition, PKC activity may be a positive or negative regulator of integrin-dependent adhesion.
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PMID:Differential regulation of chemoattractant-stimulated beta 2, beta 3, and beta 7 integrin activity. 960 68

The microenvironment of secondary lymphoid organs consists of two major populations of cells, the lymphoid cells and a population of stromal cells that contribute to both tissue architecture and function. Interactions of both populations are essential for the development and control of humoral immune responses. In this study, stromal-cell preparations were obtained by a multistage process. This involved culturing 300-400-microm slices of human tonsil for 6-8 days at 25 degrees C, trypsin digestion of the residual explant, followed by CD45-positive-cell depletion using magnetic beads, and a final period of culture for 4 days to remove remaining nonadherent cells. Phenotyping with a panel of monoclonal antibodies revealed that the cells express HLA-DR, CD54 (ICAM-1), CD44, but no CD45 nor a range of other markers for epithelial and endothelial cells. Immunoassays of supernatants from stromal cells revealed that IL-6 was produced constitutively, and its production was increased by treatment with TNF-alpha and IFN-gamma. In contrast IL-1, IL-2, IL-4, IL-7, IL-8, IL-10, IL-12, TNF-alpha, and IFNgamma were not produced. Functional tests showed that these cells express follicular dendritic cell-like properties. Coculturing of tonsilar B cells with stromal cells resulted in enhanced proliferation and also led to increased production of immunoglobulins and IL-6, suggesting crucial signaling between these populations.
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PMID:Tonsil stromal-cell lines expressing FDC-like properties: isolation, characterization, and interaction with B lymphocytes. 981 1

The homing of lymphocytes to secondary lymphoid organs is thought to involve the action of chemokines. Secondary lymphoid-tissue chemokine (SLC), a high endothelial venule (HEV)-associated chemokine, has emerged as a candidate for participating in this process. We now show that immobilized SLC strongly induces beta2 integrin-mediated binding of T lymphocytes of naive phenotype and B lymphocytes to ICAM-1 under static conditions. This effect is not mediated by beta2 integrin affinity modulation, because SLC does not elicit a beta2 integrin activation epitope (mAb24) on naive T lymphocytes. In a parallel plate flow chamber, lymphocytes rolling via L-selectin are rapidly arrested through beta2 integrins in a pertussis toxin-sensitive manner on a substrate consisting of L-selectin ligands (peripheral lymph node addressins) together with ICAM-1 and SLC. Naive T lymphocytes are arrested on the HEV substrate with sixfold higher efficiency than memory cells. Neutrophils roll, but are not arrested by SLC, whereas they respond to immobilized IL-8 with rapid arrest. Thus, our artificial HEV system recapitulates critical features of lymphocyte interactions with HEV in vivo. These observations strongly point to the participation of SLC in homing of lymphocytes to secondary lymphoid organs.
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PMID:A high endothelial cell-derived chemokine induces rapid, efficient, and subset-selective arrest of rolling T lymphocytes on a reconstituted endothelial substrate. 983 23

In these studies, we compared the phenotype, function, and expression of type 1, type 2, and monocyte-associated cytokine mRNA transcripts in autologous bone marrow (BM) and growth factor-mobilized peripheral blood stem cell (PSC) products. These studies demonstrate that lymphocytes and monocytes in stem cell products are abnormally activated, expressing significantly higher levels of interleukin (IL)-2, 4 and 10, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), but not IL-8, as compared to normal peripheral blood mononuclear cells (PBMC). In addition, the levels of IL-2, IL-10 and TNF-alpha are significantly higher in mobilized PSC as compared to BM products. The high cytokine levels are unexpected as T cell function in stem cell products is depressed. PSC products have high levels of T cell inhibitory activity, which directly correlates with IL-10 expression, both of which are mechanisms that might be involved in the immune dysfunction within stem cell products used for autologous stem cell transplantation. These data demonstrate that: (1) immune cells in autologous BM and PSC products are activated with the expression of high levels of type 1 and type 2 cytokines as well as monokines; (2) PSC products contain a high frequency of monocytes which mediate T cell inhibitory activity; and (3) despite the high levels of cytokine expression, T cell function in stem cell products is depressed. The significance of these immune abnormalities within stem cell products for myeloid and lymphoid recovery following autologous stem cell transplantation remains to be determined.
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PMID:Immunoregulatory cytokines in bone marrow and peripheral blood stem cell products. 1003 51

All leukocytes express the cell surface glycoprotein CD45, which has intrinsic intracellular protein tyrosine phosphatase activity. CD45 is known to play a regulatory role in activation-induced signaling in lymphocytes; however, little is known of its role in non-lymphoid leukocytes. Therefore, we examined the potential effect of CD45 on chemokine-induced signaling in human neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB antibody (Bra11) down-modulated expression of the chemokine receptors CXCR1 and CXCR2 to 44 +/- 10% and 47 +/- 9% of their respective controls. The tyrosine kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11-induced down-modulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were functionally inhibited in their capacity to exhibit IL-8-induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N-formyl-Met-Leu-Phe (fMLP) receptor expression and function were not lost following Bra11 treatment. The effect of Bra11 on IL-8-mediated function and receptor expression was paralleled by decreased tyrosine phosphorylation of a 54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN responses to chemokines; thus agents regulating CD45 can potentially modulate leukocyte traffic and may represent a novel therapeutic approach towards the treatment of inflammatory diseases.
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PMID:CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes. 1035

When naive T lymphocytes are activated and differentiate into memory/effector cells, they down-regulate receptors for constitutive chemokines such as CXCR4 and CCR7 and acquire receptors for inflammatory chemokines such as CCR3, CCR5 and CXCR3, depending on the Th1/Th2 polarization. This switch in chemokine receptor usage leads to the acquisition of the capacity to migrate into inflamed tissues. Using RNase protection assays, staining with specific antibodies, and response to recombinant chemokines, we now show that following TCR stimulation, memory/effector T cells undergo a further and transient switch in receptor expression. CCR1, CCR2, CCR3, CCR5, CCR6 and CXCR3 are down-regulated within 6 h, while CCR7, CCR4, CCR8 and CXCR5 are up-regulated for 2 to 3 days. Up-regulation of CCR7 following TCR stimulation was observed also among resting peripheral blood T cells and required neither co-stimulation nor exogenous IL-2. On the other hand IL-2 down-regulated CXCR5, up-regulated CCR8 and facilitated the recovery of CCR3 and CCR5. Upon TCR stimulation, Th1 and Th2 cells produced comparable sets of chemokines, including RANTES, macrophage inflammatory protein-1beta, I-309, IL-8 and macrophage-derived chemokine, which may modulate surface chemokine receptors and contribute to cell recruitment at sites of antigenic recognition. Altogether these results show that following TCR stimulation effector/memory T cells transiently acquire responsiveness to constitutive chemokines. As a result, T cells that are activated in tissues may either recirculate to draining lymph nodes or migrate to nearby sites of organized ectopic lymphoid tissues.
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PMID:Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. 1038 67

Malignant lymphocyte migration into and within lymphoreticular tissue is an important aspect of chronic lymphocytic leukemia (CLL), yet little is known about the processes involved. Our previous studies of integrin expression and function in CLL have shown that the abnormal cells are relatively nonadhesive and nonmotile on the protein ligands of these receptors. Here we show that CLL cells adhere to a non-protein ligand, hyaluronan (HA), and become motile (as assessed by both Boyden chamber migration and time-lapse video microscopy) on this ligand when stimulated with interleukin (IL) 8. The combined presence of HA and IL-8 was essential for this motility because IL-8 did not stimulate movement on other surfaces. Blocking antibodies showed that this motility is mediated by the receptor for HA-mediated motility (RHAMM), without the involvement of CD44. Moreover, confocal microscopy showed a polarized distribution of RHAMM and F-actin, but not CD44, in cells which had become motile on HA in the presence of IL-8. Immunohistochemical studies of nodes and spleen demonstrated an abundant reticular network of HA-containing fibers throughout diseased nodes and in splenic white pulp. The splenic red pulp and the luminal surface of high endothelial venules lacked HA. IL-8 was ubiquitously present in these tissues. CLL cells were shown to move spontaneously on fibroblast monolayers derived from lymphoid tissue; this movement was largely blocked by hyaluronidase or anti-RHAMM or anti-IL-8 antibodies. These studies indicate that IL-8-induced motility on HA is likely to be important for CLL cell migration through lymphoid tissue.
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PMID:The role of hyaluronan and interleukin 8 in the migration of chronic lymphocytic leukemia cells within lymphoreticular tissues. 1048 92


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