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1.
Recombinant interferon-gamma induces interleukin 2 receptors on human peripheral blood monocytes 总被引:12,自引:0,他引:12
W Holter R Grunow H Stockinger W Knapp 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(6):2171-2175
The present report describes the inducibility of IL 2 receptors on human peripheral blood monocytes. Although freshly isolated monocytes are IL 2 receptor negative, approximately one-third of the cells react with the anti-Tac antibody within 18 hr of culture. IFN-gamma is found to double both the number of positive cells and the number of binding sites, whereas IL 2 has no influence on the IL 2 receptor expression on monocytes. Anti-Tac precipitates from monocyte lysates several protein bands of similar m.w. to those previously found with activated T and B cells. Finally, IFN-gamma-induced, but not resting, monocytes are found to bind recombinant IL 2. We conclude that IFN-gamma induces peripheral blood monocytes to express IL 2 receptors similar in structure to those found on activated T and B lymphocytes. 相似文献
2.
Expression of functional IL 2 receptors by lipopolysaccharide and interferon-gamma stimulated human monocytes 总被引:21,自引:0,他引:21
W Holter C K Goldman L Casabo D L Nelson W C Greene T A Waldmann 《Journal of immunology (Baltimore, Md. : 1950)》1987,138(9):2917-2922
Human peripheral blood monocytes were stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) alone or in combination. Stimulated but not resting monocytes displayed the Tac peptide of the interleukin 2 (IL 2) receptor within 24 hr as measured by immunofluorescence staining and [3H] Tac binding. The total number of anti-Tac binding sites on co-stimulated monocytes was 13,700. By using scatchard analysis with radiolabeled IL 2, the activated cells were shown to express low numbers (below 100 sites/cell) of high affinity binding sites with a KD of approximately 15 pM. LPS and IFN-gamma were additive in augmenting the number of IL 2 and anti-Tac binding sites. By using an ELISA assay specific for the soluble released form of the Tac peptide we identified 112 U/ml of IL 2 receptors in the supernatant of monocytes stimulated for 24 hr with IFN-gamma, 233 U/ml after stimulation with LPS, and 519 U/ml after the addition of both stimulating agents. Both the membrane form (55,000 daltons), as well as the soluble form (45,000 to 50,000 daltons) of the Tac, IL 2 receptor, peptide from monocytes were shown by immunoprecipitation and gel electrophoresis to be similar size to the comparable forms of these receptors derived from activated T cells. In addition, monocytes stimulated for 8 hr contained mRNA specifically hybridizing to a cDNA probe coding for the Tac peptide. Finally, activated monocytes responded to the addition of recombinant IL 2 by an increase in H2O2 production that was measured by using fluorescent indicator 2,7-dichlorofluorescein. This response as well as the observed induction of monocytic IL 2 receptors by LPS may point to a functional role for this receptor during monocyte/macrophage responses to microbial infections. 相似文献
3.
Bacterial lipopolysaccharide-induced interferon-gamma production: roles of interleukin 1 and interleukin 2 总被引:17,自引:0,他引:17
J Le J X Lin D Henriksen-DeStefano J Vilcek 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(12):4525-4530
Bacterial lipopolysaccharide (LPS) induced human peripheral blood mononuclear cells (PBMC) to produce interferon-gamma (IFN-gamma). Monocytes play a mandatory accessory role in this process, because purified T lymphocytes failed to produce IFN-gamma in response to LPS and the addition of 2% monocytes to T cell cultures resulted in an optimal LPS-induced IFN-gamma production. IFN-gamma production was abolished in the presence of monoclonal antibodies specific for HLA-DR antigen. Addition of exogenous interleukin 2 (IL 2) markedly enhanced IFN-gamma secretion by PBMC induced with LPS. The addition of anti-Tac antibody specific for IL 2 receptors abrogated IFN-gamma production, suggesting that an interaction of IL 2 with IL 2 receptors was involved. By using a specific antibody binding assay, LPS was shown to amplify IL 2 receptor expression on PBMC, whereas exogenous IL 2 showed only a negligible enhancing effect on the expression of its own receptors. Interleukin 1 (IL 1), a product of LPS-stimulated monocytes, potentiated IL 2-induced IFN-gamma production in the absence of LPS. Neither IL 1 nor IL 2 alone induced IFN-gamma production in purified T lymphocyte cultures. When added together, however, substantial levels of IFN-gamma were induced. An enhanced IL 2 receptor expression on T cells was also demonstrated as a result of the combined action of IL 1 and IL 2. These results suggest that induction of IFN-gamma by LPS is due mainly to the generation of IL 1 and an enhanced expression of IL 2 receptors. 相似文献
4.
The role of interleukin 2 (IL 2) on the expression of IL 2 receptors and on the synthesis of gamma-interferon (gamma-IFN) by human thymocytes was investigated. Human thymocytes isolated from specimens obtained during cardiac surgery of infants and children were induced with one or all of the following agents: IL 2, concanavalin A (Con A), and 12-O-tetradecanoylphorbol 13-acetate (TPA). The expression of IL 2 receptors and gamma-IFN titers were determined. The results indicate that thymocytes cultured in complete medium do not express receptors for IL 2, nor did IL 2 by itself induce the expression of IL 2 receptors. Con A induced the expression of IL 2 receptors by a moderate number of the thymocyte population and induced the synthesis of low amounts of gamma-IFN. Preincubation of thymocytes with TPA increased the response to Con A; both the number of thymocytes expressing receptors and the synthesis of gamma-IFN were increased. Addition of IL 2 to these cultures further augmented the expression of IL 2 receptors and gamma-IFN synthesis and resulted in the optimal expression of IL 2 receptors and maximal gamma-IFN synthesis. The expression of IL 2 receptors could be detected within 24 hr and preceded the induction of proliferation; it was therefore probably not due to the clonal expansion of a population of receptor-bearing thymocytes. Conversely, inhibition of IL 2 synthesis with dexamethasone (Dex) by thymocytes activated with Con A, or inhibition of the function of IL 2 receptors by anti-Tac, resulted in a decrease in the number of IL 2 receptor-bearing thymocytes activated with Con A, or inhibition of the function of IL 2 receptors by anti-Tac, resulted in a decrease in the number of IL 2 receptor-bearing thymocytes and of gamma-IFN synthesis. Thymocytes activated with TPA and Con A were more resistant to the inhibitory effects of Dex on the expression of IL 2 receptors than thymocytes activated with Con A alone. Maximal inhibition of the expression of IL 2 receptors and of gamma-IFN synthesis was achieved as a result of the synergistic effect of anti-Tac with Dex. Therefore, when IL 2 was prevented from binding to the receptors, and IL 2 synthesis was inhibited, the number of thymocytes expressing IL 2 receptors was sharply reduced and gamma-IFN synthesis was markedly inhibited.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
5.
Monoclonal antibody OKT11A inhibits and recombinant interleukin 2 (IL 2) augments expression of IL 2 receptors at a pretranslational level 总被引:3,自引:0,他引:3
J C Reed W C Greene R G Hoover P C Nowell 《Journal of immunology (Baltimore, Md. : 1950)》1985,135(4):2478-2482
The expression of receptors for interleukin 2 (IL 2) represents a critical event regulating the growth of normal T lymphocytes. We investigated the effects of the inhibitory monoclonal antibody OKT11A (anti-sheep erythrocyte receptor) and of purified recombinant IL 2 (rIL 2) on the expression of IL 2 receptors by activated T cells at both the protein and the mRNA levels. Adding OKT11A antibody (0.5 microgram/ml) to phytohemagglutinin (PHA)-stimulated cultures of human peripheral blood mononuclear cells (PBMC) markedly suppressed cellular proliferation (assessed by [3H]thymidine incorporation) and IL 2 receptor expression (determined by immunofluorescence assay by using the anti-IL 2-receptor antibody, anti-Tac). Northern blot analysis performed with the use of a cDNA probe specific for the human IL 2 receptor gene demonstrated that OKT11A antibody also decreased the accumulation of IL 2 receptor mRNA induced by PHA in PBMC. Purified rIL 2 (10 U/ml) alone had little effect on the expression of IL 2 receptors in unstimulated PBMC cultures. In combination with PHA or with PHA plus OKT11A, however, rIL 2 augmented both the expression of IL 2 receptor protein on PBMC and the accumulation of IL 2 receptor mRNA in PBMC. Adding anti-Tac antibody to PBMC cultures to block the interaction of IL 2 with its receptor diminished the accumulation of IL 2 receptor mRNA induced by PHA. Taken together, these data demonstrate that OKT11A antibody inhibits and IL 2 augments expression of IL 2 receptors on PHA-stimulated T cells, at least in part, at a pretranslational level. 相似文献
6.
Regulation of interleukin 2 receptor expression: effects of phorbol diester, phospholipase C, and reexposure to lectin or antigen 总被引:21,自引:0,他引:21
J M Depper W J Leonard M Kr?nke P D Noguchi R E Cunningham T A Waldmann W C Greene 《Journal of immunology (Baltimore, Md. : 1950)》1984,133(6):3054-3061
Anti-Tac monoclonal antibody identifies the receptor for interleukin 2 (IL 2, or T cell growth factor) present on activated human T lymphocytes. By using tritiated anti-Tac, we now report a sensitive and specific binding assay to evaluate cell surface IL 2 receptor expression. IL 2 receptors on human peripheral blood lymphocytes can be detected within 6 hr after PHA stimulation. PHA-induced receptor expression is inhibited by actinomycin D and cycloheximide, but not by mitomycin C, suggesting a requirement for de novo RNA and protein synthesis, but not DNA synthesis. Scatchard analysis of [3H]-anti-Tac binding to lymphocytes stimulated with PHA for 3 days revealed from 20,000 to 60,000 molecules of antibody bound per cell, and a Kd of 1 to 3 x 10(-10) mol/l. Sequential binding studies of activated human lymphocytes maintained in long-term culture with IL 2 demonstrated a progressive decline in receptor number correlating with diminished growth rate. Restimulation with lectin or antigen increased the number of IL 2 receptors, suggesting that IL 2 dependent immune responses may be regulated, at least in part, by IL 2 receptor expression. Receptor number was also increased by PMA. Moreover, similar effects were produced by incubation with phospholipase C but not interleukin 1. Because both PMA and phospholipase C result in activation of protein kinase C, these data suggest the possibility that activation of protein kinase C may induce IL 2 receptor expression. 相似文献
7.
Tac antigen (as a measure of the IL 2 receptor) acquisition and regulation by IL 2, an antigen-receptor agonist (anti-T3), phorbol esters, and phytohemagglutinin (PHA) were studied. Phorbol esters stimulated de novo acquisition of Tac antigen, which was associated with the subcellular redistribution of protein kinase C (PK-C) from cytosol to particulate membranes of human T lymphocytes. PHA and anti-T3 (alpha-T3) antibody also stimulated a transient redistribution and activation of PK-C that reached a maximum within 20 min after stimulation. Both phorbol esters and alpha-T3 could increase Tac expression and stimulate PK-C translocation on 5 and 12 day activated T cells that were at the G0/G1 stage of the cell cycle due to IL 2 deprivation. Tac antigen-specific mRNA was seen in the nucleus within 2 hr after stimulation. In contrast, IL 2 alone could only increase Tac expression and stimulate PK-C translocation on day 5 but not day 12 activated T cells. IL 2 synergizes with alpha-T3 and phorbol ester for the regulation of Tac expression. Although IL 2 increased expression of Tac, the majority if not all of these receptors possessed low affinity for IL 2. These data suggest that the activation of PK-C is a common transmembrane signal shared by IL 2 and antigen stimulation. The results also imply that PK-C activation is necessary for the regulation of Tac antigen expression. 相似文献
8.
S Koyasu J Yodoi T Nikaido Y Tagaya Y Taniguchi T Honjo I Yahara 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(3):984-987
Several mouse IL 3-dependent cell lines, IC2, LT4, FDC-P2, and PB-3C, derived from spleen or bone marrow cells were shown to express low affinity receptors for IL 2 (Kd; 0.5 to 8 X 10(-8) M). High affinity receptors for IL 2 were not detected on the IL 3-dependent cells within the experimental limitation of this study. The clones did not respond to IL 2 at all at the concentration as high as 25 micrograms/ml. The number of the receptors expressed on those clones was estimated to be 0.2 to 2 X 10(5)/cell, which is comparable with the number of those on IL 2-dependent T cell clones. Expression of IL 2 receptor was confirmed in mRNA levels for both IC2 and LT4 cells. A relatively low level expression of one (4.5 Kb) of four IL 2 receptor mRNA species was observed with those IL 3-dependent clones compared with IL 2-dependent T cells. It seems that these low affinity receptors may be expressed on IL 3-dependent cells that undergo differentiation or maturation in mast cell and some myeloid cell lineages. 相似文献
9.
Y Jacques B Le Mauff A Godard D Olive J F Moreau J P Soulillou 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(5):1693-1699
A human T cell clone (termed 40.2.6) established from a rejected human kidney allograft has been studied for its ability to express membrane IL 2 receptors in response to antigen (irradiated cells from the graft's donor) and recombinant IL 2 (rec-IL 2). On antigenic stimulation, the 40.2.6 clone produced low levels (0.15 U/ml) of IL 2 (peak at 24 hr) and incorporated (3H)thymidine (peak at 48 hr). This incorporation was strongly enhanced on addition of rec-IL 2 and was inhibited by the 33B31 antibody, an anti-human IL 2 receptor monoclonal antibody (Mab). The 125I-labeled 33B31 Mab has been used to quantify the density of IL 2 receptors on 40.2.6 cells. Cells not re-exposed to antigen or rec-IL 2 had a level of 33B31-binding sites which declined rapidly (10% of starting value after 2 days). This level remained much more stable when rec-IL 2 (1 U/ml) was present in the medium (80% at day 2). Antigen induced a three- to eightfold increase in the level of 33B31-binding sites which peaked at 24 hr and then declined. When a similar antigenic stimulation was performed in the presence of rec-IL 2 (1 U/ml), the level of 33B31-binding sites peaked at a higher value (eight- to 20-fold increase at day 2), and its subsequent decline was slower. These potentiating effects of rec-IL 2 were dose-dependent and occurred at low concentrations corresponding to the saturation by rec-IL 2 of high affinity IL 2 receptor sites. Finally, high affinity IL 2 receptors, as measured by the binding of 35S-labeled rec-IL 2, were found to be similarly up-regulated by antigen and rec-IL 2. Together, our results obtained on a monoclonal human T cell population with highly purified rec-IL 2 demonstrate that rec-IL 2 and antigen act in synergy to induce the expression of both high and low affinity membrane IL 2 receptors. 相似文献
10.
N Kumagai S H Benedict G B Mills E W Gelfand 《Journal of immunology (Baltimore, Md. : 1950)》1988,140(1):37-43
The proliferation of human T lymphocytes is regulated, in part, by the coordinated expression of genes encoding T cell growth factor (interleukin 2 (IL-2), IL-2 receptors, and transferrin receptors (TFR). We examined the time course of accumulation of mRNA for these genes in T cells stimulated with the phorbol ester, phorbol 12,13-dibutyrate (PDB) and the calcium ionophore, ionomycin, and compared their expression to T cells stimulated with phytohemagglutinin. In cells treated with PDB/ionomycin, maximum expression was observed at 3 hr for IL-2 mRNA and at 6 hr for TFR mRNA, whereas the level of IL-2 receptor mRNA reached a peak 24 to 48 hr after stimulation. In phytohemagglutinin-stimulated T cells IL-2 mRNA was detectable within 3 hr but peaked later at 12 hr; the level of IL-2 receptor mRNA similarly peaked 24 to 48 hr later. Accumulation of TFR mRNA in phytohemagglutinin-stimulated T cells, however, was not detectable at 6 hr and reached a peak only between 12 to 24 hr. The early accumulation of TFR mRNA in PDB/ionomycin-stimulated T cells seemed, in part, independent of the interaction of IL-2 with its own receptor, because TFR mRNA was detectable as early as 1 hr after stimulation and addition of cycloheximide before addition of PDB/ionomycin did not abolish the PDB/ionomycin-induced accumulation of TFR mRNA. In addition, either PDB or ionomycin used alone induced the expression of TFR mRNA but not IL-2 mRNA. These results indicated that the combination of PDB/ionomycin accelerated the expression of IL-2 and TFR genes in T cells compared to phytohemagglutinin and triggered an IL-2-independent pathway for the induction of TFR mRNA. 相似文献
11.
Lipopolysaccharide and interleukin 1 inhibit interferon-gamma-induced Fc receptor expression on human monocytes 总被引:5,自引:0,他引:5
W P Arend J T Ammons B L Kotzin 《Journal of immunology (Baltimore, Md. : 1950)》1987,139(6):1873-1879
The objectives of these studies were to study the effects of bacterial lipopolysaccharide (LPS) on interferon-gamma (IFN-gamma)-induced Fc receptor expression on human monocytes and to examine whether these effects were mediated through stimulation of interleukin 1 (IL-1) production. Fc receptor expression was determined by binding of monomeric monoclonal murine immunoglobulin (Ig)G2a and cytofluorographic analysis. IL-1 activity in monocyte supernatants and lysates was assayed by augmentation of mitogen-induced murine thymocyte proliferation. IFN-gamma induced the expression of Fc receptors on human monocytes that were specific for murine IgG2a. This induction was inhibited by the addition of LPS in amounts as low as 2 to 8 pg/ml. LPS inhibition of IFN-gamma-induced Fc receptor expression was paralleled by the appearance of IL-1 in monocyte lysates and supernatants. The addition of purified human or recombinant IL-1 beta at the initiation of culture similarly inhibited the expression of IFN-gamma-induced Fc receptors on the monocytes. LPS also inhibited Fc receptor expression on the human myelomonocytic cell line THP-1 after induction with IFN-gamma or phorbol myristate acetate alone or with both agents together. This inhibition also was paralleled by the production of IL-1 but the addition of exogenous IL-1 to the THP-1 cells had no effect on IFN-gamma-induced Fc receptor expression. Tumor necrosis factor (TNF) inhibited IFN-gamma-induced Fc receptor expression on human monocytes but was much less potent than comparable amounts of IL-1. TNF also did not inhibit Fc receptor expression on THP-1 cells. In fact, IL-1 or TNF led to an enhancement in IFN-gamma-induced Fc receptor expression on THP-1 cells. These results indicate that LPS can inhibit IFN-gamma-induced Fc receptor expression on human monocytes and that IL-1 and TNF may mediate these effects of LPS. Thus, an autocrine or paracrine role is suggested for these cytokines. The possibility exists that intracellular IL-1 resulting from LPS stimulation may be at least in part responsible for inhibition of Fc receptor expression. 相似文献
12.
T Gatanaga C D Hwang M Gatanaga F Cappuccini R S Yamamoto G A Granger 《Cellular immunology》1991,138(1):1-10
The regulation of the 55-kDa TNF receptor (TNF-R) mRNA synthesis, membrane expression, and TNF binding factor (BF) release was examined in resting and activated human monocytic THP-1 and human promyelocytic leukemia HL-60 cells in vitro. Cells were activated with phorbol myristate acetate (PMA) and bacterial lipopolysaccharide (LPS). TNF alpha cytolytic activity in the supernatant of THP-1 cells stimulated by PMA began to appear at 4 hr, reached a peak at 8 hr, and declined by 12 hr. For THP-1 cells stimulated with LPS, the peak of TNF alpha activity appeared at 4 hr and then declined. TNF alpha-binding sites on the cell membrane were down-regulated within 1 hr after PMA and LPS treatment and then reappeared 12 hr later. Fifty-five-kilodalton TNF-R mRNA expression during this time period did not correlate with the level of membrane TNF-binding site expression. Additional studies indicated the presence of a 30-kDa TNF-BF in the supernatants which appeared after 24 hr. These data suggest that activated THP-1 and HL-60 cells are capable of releasing TNF-BF into the supernatant and this material may be involved in the control of secreted TNF alpha activities. 相似文献
13.
K Matsushima M Taguchi E J Kovacs H A Young J J Oppenheim 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(8):2883-2891
The production of interleukin (IL 1) by normal human peripheral blood monocytes purified by Ficoll-Hypaque density sedimentation, Percoll-gradient sedimentation, and plastic adherence can be detected as early as 30 min intracellularly, and extracellularly within 1 hr after stimulation with lipopolysaccharide (LPS). Production of mRNA coding for the isoelectric point 7.0 species of IL 1 was also detected as early as 1 hr after LPS stimulation and reached a maximum level at 6 hr. Cell-associated IL 1 activity could be extracted with CHAPS detergent from every cell fraction (i.e., membranes, cytosol, and particulates), but was present mainly (greater than 95%) in the cytosol of LPS-activated monocytes and the myelomonocytic cell line, THP-1. The apparent m.w. of IL 1 activity on high pressure liquid chromatography gel filtration in every cell fraction was approximately 23,000 daltons, with a minor peak at 31,000 daltons, whereas the IL 1 activity in the culture supernatants was 17,000 daltons. Western blotting analysis of LPS-stimulated monocyte extracts showed two forms of IL 1 corresponding to 31,000 daltons and 25,000 daltons. Exposure of viable cells to trypsin and plasmin released biologically active 23,000 dalton IL 1 only from IL 1-producing cells such as activated monocytes and IL 1-producing Ebstein-Barr virus B lymphocyte cell lines. Consequently, biologically active IL 1 is presumably exposed on the outer surface of cell membranes. Furthermore, IL 1 release by human monocytes in plasminogen-depleted fetal calf serum was considerably decreased. Conversely, supplementation of plasminogen-depleted serum with purified plasminogen restored the IL 1 production, suggesting that plasmin or plasmin-like factors may be involved in the regulation of the release of IL 1 from IL 1-producing cells. In conclusion, the results suggest that IL 1 is rapidly produced, is pooled in the cytosol, and in part is processed by enzymes, is transferred to the plasma membranes, and is then released from the cells. Tissue plasminogen activator and serum enzymes such as plasmin may therefore be involved in the release of IL 1 from IL 1-producing cells. 相似文献
14.
Antigen-dependent regulation of interleukin 2 receptor expression on cloned human cytotoxic T lymphocytes 总被引:5,自引:0,他引:5
D R Kaplan V L Braciale T J Braciale 《Journal of immunology (Baltimore, Md. : 1950)》1984,133(4):1966-1969
IL 2 receptor expression as a function of time after antigenic stimulation was examined on antigen-dependent human CTL clones specific for type A influenza virus. The anti-Tac monoclonal antibody was used to follow IL 2 receptor levels on the cloned cells. Shortly after antigenic stimulation, IL 2 receptor expression was maximal; by 1 wk, however, levels had decayed considerably, and by 2 wk only background expression remained. Reexpression of IL 2 receptors could be induced by exposure of quiescent clones to antigen or lectin. IL 2-driven proliferation of the cytotoxic clones was also examined, and it decayed with the same kinetics as IL 2 receptor levels. Proliferation of quiescent cells could also be obtained by antigen-specific stimulation. Thus, IL 2 receptor expression by human CTL clones at least in part regulates the antigen-specific proliferation of these cells. 相似文献
15.
16.
Activation of virus specific CTL clones: antigen-dependent regulation of interleukin 2 receptor expression 总被引:4,自引:0,他引:4
M E Andrew A M Churilla T R Malek V L Braciale T J Braciale 《Journal of immunology (Baltimore, Md. : 1950)》1985,134(2):920-925
Interleukin 2 (IL 2) is a lymphocyte-specific growth hormone, whose effect on lymphocyte proliferation is exerted through a cell surface receptor expressed on activated lymphocytes. In this report we have used monoclonal antibodies directed to the murine IL 2 receptor to examine the regulation of the IL 2 receptor expression on cloned populations of influenza virus-specific CTL. The CTL clones, which are dependent on both specific antigenic stimulation and exogenous IL 2 for continuous in vitro propagation, express high levels of the IL 2 receptor shortly after antigenic stimulation (day 2 or 3). Over the next 5 to 8 days of in vitro cultivation in IL 2-containing medium, these cloned CTL cells express decreasing levels of IL 2 receptor. Concomitant with this fall in IL 2 receptor expression, the cells become refractory to the IL 2 proliferative stimulus. The cloned cells remain refractory to IL 2 until specifically stimulated by antigen, which induces high levels of the IL 2 receptor on the cells and renders the cells sensitive to IL 2 once again. These results support the concept that IL 2 receptor expression on activated T lymphocytes is transitory and that receptor expression is endogenously regulated in the activated T lymphocytes. These results also suggest that antigen plays a primary role in regulating T lymphocyte proliferation by maintaining IL 2 receptor levels. 相似文献
17.
Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells 总被引:13,自引:0,他引:13
Medvedev AE Lentschat A Wahl LM Golenbock DT Vogel SN 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(9):5209-5216
Prior exposure to LPS induces a transient state of cell refractoriness to subsequent LPS restimulation, known as endotoxin tolerance. Induction of LPS tolerance has been reported to correlate with decreased cell surface expression of the LPS receptor complex, Toll-like receptor 4 (TLR4)/MD-2. However, other results have underscored the existence of mechanisms of LPS tolerance that operate downstream of TLR4/MD-2. In the present study we sought to delineate further the molecular basis of LPS tolerance by examining the TLR4 signaling pathway in endotoxin-tolerant cells. Pretreatment of human monocytes with LPS decreased LPS-mediated NF-kappaB activation, p38 mitogen-activated protein kinase phosphorylation, and TNF-alpha gene expression, documenting the induction of endotoxin tolerance. FACS and Western blot analyses of LPS-tolerant monocytes showed increased TLR2 expression, whereas TLR4 expression levels were not affected. Comparable levels of mRNA and protein for myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase 1 (IRAK-1), and TNFR-associated factor-6 were found in normal and LPS-tolerant monocytes, while MD-2 mRNA expression was slightly increased in LPS-tolerant cells. LPS induced the association of MyD88 with TLR4 and increased IRAK-1 activity in medium-pretreated cells. In LPS-tolerant monocytes, however, MyD88 failed to be recruited to TLR4, and IRAK-1 was not activated in response to LPS stimulation. Moreover, endotoxin-tolerant CHO cells that overexpress human TLR4 and MD-2 also showed decreased IRAK-1 kinase activity in response to LPS despite the failure of LPS to inhibit cell surface expression of transfected TLR4 and MD-2 proteins. Thus, decreased TLR4-MyD88 complex formation with subsequent impairment of IRAK-1 activity may underlie the LPS-tolerant phenotype. 相似文献
18.
Inorganic arsenic, a well-known Nrf2 inducer, exerts immunosuppressive properties. In this context, we recently reported that the differentiation of human blood monocytes into immature dendritic cells (DCs), in the presence of low and noncytotoxic concentrations of arsenic, represses the ability of DCs to release key cytokines in response to different stimulating agents. Particularly, arsenic inhibits the expression of human interleukin-12 (IL-12, also named IL-12p70), a major proinflammatory cytokine that controls the differentiation of Th1 lymphocytes. In the present study, we determined if Nrf2 could contribute to these arsenic immunotoxic effects. To this goal, human monocyte-derived DCs were first differentiated in the absence of metalloid and then pretreated with arsenic just before DC stimulation with lipopolysaccharide (LPS). Under these experimental conditions, arsenic rapidly and stably activates Nrf2 and increases the expression of Nrf2 target genes. It also significantly inhibits IL-12 expression in activated DCs, at both mRNA and protein levels. Particularly, arsenic reduces mRNA levels of IL12A and IL12B genes which encodes the p35 and p40 subunits of IL-12p70, respectively. tert-Butylhydroquinone (tBHQ), a reference Nrf2 inducer, mimics arsenic effects and potently inhibits IL-12 expression. Genetic inhibition of Nrf2 expression markedly prevents the repression of both IL12 mRNA and IL-12 protein levels triggered by arsenic and tBHQ in human LPS-stimulated DCs. In addition, arsenic significantly reduces IL-12 mRNA levels in LPS-activated bone marrow-derived DCs from Nrf2+/+ mice but not in DCs from Nrf2−/− mice. Finally, we show that, besides IL-12, arsenic significantly reduces the expression of IL-23, another heterodimer containing the p40 subunit. In conclusion, our study demonstrated that arsenic represses IL-12 expression in human-activated DCs by specifically stimulating Nrf2 activity. 相似文献
19.
Leukotrienes augment interleukin 1 production by human monocytes 总被引:18,自引:0,他引:18
The effects of leukotrienes (LT) on production of interleukin 1 (IL 1) by human peripheral blood monocytes were examined. LTB4 enhanced IL 1 production by lipopolysaccharide (LPS)-stimulated monocytes twofold to threefold, and the most efficient concentrations of LTB4 were 10(-8) to 10(-7) M. LTD4 also enhanced IL 1 production, but to a lesser extent than LTB4. Adherence-purified, but otherwise unstimulated, human monocytes could also be induced to produce IL 1 in response to LTB4. Similarly, IL 1 production by monocytes stimulated with the known IL 1 inducers muramyl dipeptide, silica, or zymosan was also enhanced by LTB4. Inhibition of cyclooxygenase with use of indomethacin during IL 1 production by LPS-treated monocytes enhanced thymocyte response to IL 1, but LTB4 further enhanced IL 1 production when added to indomethacin-treated monocyte cultures. Neither LTB4 nor indomethacin had any direct effect on thymocyte proliferation. Optimal enhancement of IL 1 production occurred when LPS and LTB4 were present together at the initiation of the 24-hr monocyte culture. Significant enhancement was also observed, however, when monocyte cultures were either preincubated with LTB4 before addition of LPS or cultured with LPS alone for 3 hr before addition of LTB4. These results indicate that leukotrienes can modulate IL 1 production by human monocytes and suggest that they may play a role in IL 1-mediated functions of monocytes in inflammatory and immune reactions. 相似文献
20.
IL-2 enhances c-fms expression in human monocytes 总被引:2,自引:0,他引:2
I Espinoza-Delgado D L Longo G L Gusella L Varesio 《Journal of immunology (Baltimore, Md. : 1950)》1990,145(4):1137-1143