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PubMed1992

Differential expression of cytokines in human blood monocyte subpopulations.

Cytokine expression was analyzed in CD14++ regular monocytes and in the novel subset of CD14+/CD16+ small monocytes. Biologic activity for tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6 in the supernatant of elutriator-enriched, cell sorter-purified small monocytes was about 10-fold lower compared with regular monocytes when stimulated with lipopolysaccharide (LPS) for 12 hours. In CD14++ regular monocytes levels were 1,157 U x 10(-3)/mL, 158 U/mL, and 1,337 U/mL for TNF, IL-1, and IL-6, respectively. By contrast, CD14+/CD16+ small monocytes exhibited 137 U x 10(-3)/mL, 14 U/mL, and 60 U/mL for TNF, IL-1, and IL-6, respectively. Additional treatment with interferon-gamma enhanced production of TNF in both subsets, but CD14+/CD16+ small monocytes still exhibited lower levels. Stimulation of the monocyte subsets by platelet-activating factor gave the same pattern of results. Hybridization with 32P-labeled oligonucleotides specific for the respective cytokine messenger RNAs (mRNAs) showed a 10-fold lower prevalence of transcripts for TNF, IL-1, and IL-6, as well. By contrast, the constitutive expression of Glyceraldehyde-3-phosphate-dehydrogenase mRNA was 1.7-fold higher in the CD14+/CD16+ small monocytes. These data indicate that the novel subset of small monocytes is selectively suppressed in the expression of the cytokines TNF, IL-1, and IL-6, suggesting that these cells may comprise a deactivated type of cell. The expression of class II transcripts in the small monocytes is, however, similar to the regular monocytes, and the cell surface expression of class II protein about threefold increased. Thus, the novel subset of small monocytes appears to be a functionally distinct type of cell.

Antigens, CD↗
PubMed1992

Expression of a monocyte chemotactic cytokine by human mononuclear phagocytes.

The present study was designed to investigate the capacity of human mononuclear phagocytes to produce a cytokine chemotactic for monocytes (monocyte chemotactic protein (MCP), alternative acronyms JE, monocyte chemotactic and activating factor, MCP-1, and tumor-derived chemotactic factor). Human PBMC exposed in vitro to bacterial LPS expressed high levels of MCP transcripts. Monocyte-depleted lymphoid cells were not induced to express MCP by LPS. Percoll-gradient purified monocytes were able to express high levels of MCP transcripts. In an effort to exclude a role of contaminating non-monocytic cells, mononuclear phagocytes were separated by flow cytometry and sorting: CD14+ cells exposed to LPS showed high levels of MCP mRNA. LPS-stimulated monocytes released chemotactic activity for monocytes that could be inhibited by absorption with anti-MCP antibodies. IL-1, TNF, IFN-gamma, granulocyte-macrophage-CSF and, to a lesser extent, macrophage-CSF, as well as inactivated streptococci, also induced MCP gene expression. Actinomycin D experiments indicated that induction of MCP in monocytes was gene transcription-dependent. The protein synthesis inhibitor cycloheximide (Cy) blocked IL-1-, TNF-, or LPS-induced MCP gene expression in monocytes. In contrast, expression of the structurally related chemotactic cytokine IL-8 was superinduced by Cy. Moreover, Cy superinduced MCP gene expression in cells other than monocytes, including endothelial cells, smooth muscle cell and fibrosarcoma cells, indicating different mechanisms of regulation in mononuclear phagocytes vs cells of other lineages. The capacity of cells of the monocyte-macrophage lineage to produce a cytokine that recruits and activates circulating monocytes may be of considerable importance in inflammatory and immunologic reactions. Thus, the mononuclear phagocyte system can autonomously regulate the extravasation and activation of immature elements of the same lineage, a key event in inflammation and immunity.

Antigens, CD↗
PubMed2004

Prevention and reversal of tumor cell-induced monocyte deactivation by cytokines, purified protein derivative (PPD), and anti-IL-10 antibody.

Upon contact with tumor cells when cocultured in vitro, human monocytes become unresponsive (deactivated) to restimulation and demonstrate decreased production of TNF-alpha and IL-12, and enhanced IL-10 secretion. The present study was undertaken to determine whether immunomodulatory agents (proinflammatory cytokines and PPD of tuberculin) could either prevent or reverse the deactivation of monocytes. Monocytes were treated with the agents either before or after being cocultured with tumor cells. Pretreatment of monocytes with IFN-gamma, either alone or in combination with TNF-alpha, GM-CSF, or PPD, significantly enhanced TNF-alpha and IL-12 production by deactivated monocytes. TNF-alpha, GM-CSF, and PPD alone were inactive. Treatment of monocytes following coculture with IFN-gamma, TNF-alpha, GM-CSF, PPD or IFN-gamma in combination with these agents reversed the depressed TNF-alpha release, whereas IL-12 production was enhanced by IFN-gamma alone. All the agents had no or only a limited effect on the enhanced IL-10 secretion by deactivated monocytes. However, treatment of cocultured monocytes with anti-IL-10 mAb significantly increased the production of TNF-alpha and IL-12 by deactivated monocytes. Moreover, coengraftment of deactivated monocytes with human pancreatic carcinoma cells into SCID mice caused an enhancement of the tumor growth that was alleviated by the treatment of monocytes in vitro with IFN-gamma alone or in combination with GM-CSF or PPD. These results suggest that activation of monocytes with certain proinflammatory cytokines and/or selective inhibition of IL-10 by a mAb may prevent or reverse monocyte deactivation caused by tumor cells.

Antibodies, Monoclonal↗
PubMed1991

CD14 contributes to the adherence of human monocytes to cytokine-stimulated endothelial cells.

Monocyte adherence to endothelial cells (EC) is selectively increased during inflammation. The mechanisms underlying monocyte-EC interaction indicated the involvement of surface-adhesion molecules on monocytes and EC. In earlier studies we noticed that the monocyte-specific mAb, designated mAb 63D3, in contrast to mAb against the beta 2-integrin molecules, inhibited the monocyte binding to monolayers of rIL-1 alpha-stimulated venous EC. The aim of the present study was to further characterize the Ag recognized by mAb 63D3 and to investigate the specific contribution of this Ag to the adherence of monocytes to cultured human macrovascular venous or arterial EC. Flow cytometric analysis demonstrated that the 63D3 Ag is expressed exclusively on the surface of peripheral blood monocytes. SDS-PAGE analysis of mAb 63D3 immunoprecipitates of 125I-labeled human monocyte surface proteins revealed that the target Ag for mAb 63D3 is a 52- to 55-kDa molecule identical to the myeloid differentiation protein CD14. Stimulation of EC with rIL-1 alpha or rTNF-alpha for 4 or 24 h or rIFN-gamma for 24 h increased (p less than 0.005) the number of monocytes bound to both types of EC. This cytokine-induced increase in monocyte adherence was significantly (p less than 0.0005) inhibited when the monocytes were coated with various mAb against CD14. The binding of monocytes to nonstimulated venous or arterial EC was not inhibited by anti-CD14 mAb. Our results lead to the conclusion that CD14 molecules, which on basis of their structure and m.w. are not related to the beta 2-integrin family of heterodimeric leukocyte adhesion molecules, participate in the binding of monocytes to cytokine-stimulated EC.

Antibodies, Monoclonal↗
PubMed1979

The role of monocytes in human lymphocyte activation by mitogens.

Studies were performed to determine the role of monocytes in human lymphocyte activation by mitogens. Velocity sedimentation at 1 x G in a new apparatus was utilized to obtain highly purified lymphocyte fractions (LF) nearly free of monocytes (0.02 to 0.4%) and a fraction (MF) enriched for monocytes (64 to 92%). The average peak responses of the lymphocyte fractions to phytohemagglutinin, concanavalin A, and pokeweed mitogen were 19, 10, and 9% of the responses achieved with unfractionated lymphocyte cultures containing approximately 20% monocytes. These changes were not attributable to altered dose requirements. When mitomycin-C-treated MF cells were used to reconstitute LF cultures, it was found that 4% monocytes fully restored the response to phytohemagglutinin whereas 8 to 16% monocytes were required for a normal response to the other mitogens. Higher numbers of MF cells produced supranormal responses, with 35 to 50% monocytes resulting in the optimal stimulation. Allogeneic monocytes were able to fully reconstitute the response of LF, and 2-mercaptoethanol (50 microM) was only slightly effective. In exploring possible mechanisms by which monocytes potentiate the mitogenic activity of lymphocytes, it was found that the supernatants of MF cultures could partially, but not completely, reconstitute LF responses, suggesting that contact with MF may be required for optimal effectiveness. Addition of graded numbers of monocytes to LF altered both the kinetics of the response and the peak level of proliferation. Monocyte depletion also resulted in markedly decreased survival of cultured unstimulated LF. These observations suggest a variety of possible effects of monocytes in potentiating mitogenic responses, including contact-mediated interactions with lymphocytes (possibly to present the mitogen optimally); enhancement of proliferation kinetics and the size of the responding subpopulation, and maintenance of a requisite growth factor(s) in the culture. Small differences in the monocyte content of cultured lymphocyte preparations may thus account for many of the often observed variations in mitogen responsiveness.

Cell Survival↗
PubMed1982

Analysis of antigenic determinants on human monocytes and macrophages.

Mo1, 2, 3, and 4, and Plt-1 are a series of five distinct antigens detected on the surface of human peripheral blood monocytes by mouse monoclonal antibodies. Mo2 and 3 are restricted to the monocyte-macrophage series, while Mo1, as previously reported, is also expressed by human granulocytes and null cells. Mo3, as distinguished from Mo1 and Mo2, is weakly expressed by virgin peripheral blood monocytes but becomes well expressed if monocytes are cultured overnight at 37 degrees C. Mo4 is coexpressed by monocytes and platelets, while Plt-1 appears to be a platelet-specific antigen whose detection on monocytes reflects adherence of platelets to monocyte membranes. That Mo2-4 are true monocyte antigens is demonstrated by their resynthesis following protease treatment of monocytes (Mol expression is resistant to proteolytic digestion). During myeloid-monocyte differentiation, the Mo antigens are infrequently expressed by immature myeloid cells but are found at higher frequency on leukemic monocytic forms. Macrophages from cultured peripheral blood monocytes and HL-60 cells exposed to lymphokines or phorbol diester express Mo1-4, but noncirculating peritoneal macrophages lack Mo3. The Mo antigens are differentiation markers whose expression reflects membrane heterogeneity during myeloid-monocyte-macrophage maturation.

Animals↗
PubMed1983

Erythromyeloid tumor cells (K562) induce PGE synthesis in human peripheral blood monocytes.

Human peripheral blood monocytes were found to spontaneously produce prostaglandin of the E series (PGE) in culture medium (0.5 ng to 3.0 ng/7.5 X 10(5) cells), and the addition of K562 tumor cells enhanced the production by five- to 15-fold after 18 hr of incubation. PGE2 (10(-6) M) inhibited the cytolytic activity of freshly isolated peripheral blood monocytes against K562 target cells by 50%. The PGE production was inhibited by inhibitors of cyclo-oxygenase (indomethacin, aspirin, and ETYA) when present during the incubation. However, pretreatment of monocytes with these cyclo-oxygenase inhibitors was ineffective in preventing PGE production. Kinetic experiments showed that appreciable stimulation of PGE production occurred only after 6 hr of co-culture. Other human tumor cell lines (HSB, SB, and CEM) enhanced PGE production upon co-culture with monocytes but to a lesser extent (twofold to threefold). Monocytes treated with 0.4% formaldehyde or heat (56 degrees C) were not capable of producing PGE when cultured alone or with K526 tumor cells. In contrast, formaldehyde-treated, but not heat-treated, K562 tumor cells were able to induce monocytes to produce PGE. By using a single cell conjugation assay, K562 tumor cells were found to bind equally well to treated or untreated monocytes. In contrast, the lytic activity of treated monocytes against K562 target cells was abolished. The presence of protein synthesis inhibitor, cycloheximide, was found to inhibit PGE production by monocytes cultured alone or with K562 tumor cells. Supernatants from K562 tumor cell cultures were also capable of inducing monocytes to produce PGE, and their effect on PGE production from monocytes was suppressed by cycloheximide. In addition, pretreatment of either K562 tumor cells or monocytes with an irreversible protein synthesis inhibitor, emetine, also suppressed the production of PGE upon co-culture with the untreated counterpart. The production of PGE by monocytes in response to exposure to tumor cells may represent a mechanism whereby tumor cells subvert host immune defense against them.

Cell Line↗
PubMed1982

Monocyte function in Hodgkin's disease.

Monocyte functions were studied in 16 patients with Hodgkin's disease, 11 untreated and five in unmaintained complete remission. Eleven untreated patients with non-Hodgkin's lymphomas and 21 healthy persons were used as controls. Monocytes were isolated from peripheral blood and enriched to greater than 90%. Lymphoma monocytes showed normal ability to lyse human RBC coated with anti-D IgG antibodies as evaluated by a 51Cr-release assay. The ability of monocytes to augment or suppress concanavalin A stimulation of lymphocytes purified to greater than 98% was studied by incubation of a number of lymphocytes with increasing amounts of purified monocytes. The incorporation of 14C-thymidine was potentiated by a factor of 10 in the presence of equal amounts of monocytes. There was no difference between monocytes from Hodgkin, non-Hodgkin or healthy controls to augment patients' autologous or normal lymphocytes. Patient monocytes also suppressed the response at the same monocyte-lymphocyte ratio as normal monocytes. Stimulation of patient lymphocytes without the addition of monocytes was usually lower than that of normal control lymphocytes. The difference between patient and control lymphocyte stimulation was preserved in the presence of monocytes. It is concluded that monocytes from patients with active Hodgkin's disease or non-Hodgkin's lymphoma have normal helper and suppressor effects on patient or normal lymphocytes stimulated by Con A and normal antibody-dependent cytotoxicity.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1995

In vivo blood monocyte migration to acute inflammatory reactions, IL-1 alpha, TNF-alpha, IFN-gamma, and C5a utilizes LFA-1, Mac-1, and VLA-4. The relative importance of each integrin.

UNLABELLED: The role of the monocyte integrins, Mac-1, LFA-1, and VLA-4, on the adhesion of rat blood monocytes to rat microvascular endothelial cells in vitro and the importance of these receptors in monocyte migration to inflammation in vivo were evaluated. Monocyte adhesion to cytokine (IL-1, IFN-gamma, and TNF-alpha)-stimulated endothelial cells was mediated by Mac-1, LFA-1, and VLA-4, but Mac-1 appeared to be less important than LFA-1 or VLA-4. After i.v. injection, large numbers of 51Cr-labeled blood monocytes migrated within 2 h to dermal inflammatory sites induced by C5a, IL-1 alpha, IFN-gamma, TNF-alpha, LPS, and poly inosinic:cytidylic acid. Anti-Mac-1 mAb treatment had no effect, whereas anti-LFA-1 inhibited migration to C5a and the cytokines by 20 to 40%. Blocking both Mac-1 and LFA-1 decreased monocyte accumulation by 50 to 70% to all stimuli. Anti-VLA-4 inhibited monocyte migration to IL-1 alpha, IFN-gamma, TNF-alpha, and LPS, but not to C5a. Combining anti-Mac-1 with anti-VLA-4 did not increase this inhibition, whereas blocking VLA-4 and LFA-1 together further suppressed (60-85%) migration. Combined treatment with mAb to all three integrins inhibited > 98% of the monocyte migration to the inflammatory stimuli. IN CONCLUSION: 1) 51Cr blood monocytes can be used to quantify monocyte migration to inflammatory reactions in the rat. 2) Monocytes use Mac-1, LFA-1, and VLA-4 for in vitro adhesion and in vivo migration to cutaneous inflammation, and these integrins are essential for normal migration because blockade of all three virtually abolishes monocyte accumulation. 3) Mac-1 plays a less important role than LFA-1, as LFA-1 appears to substitute for Mac-1, and VLA-4 and LFA-1 can mediate much of the adhesion and migration. 4) The initiating inflammatory stimulus also modifies monocyte integrin usage, supporting the multistep combinatorial model of leukocyte extravasation.

Animals↗
PubMed1995

A regulatory role for astrocytes in HIV-1 encephalitis. An overexpression of eicosanoids, platelet-activating factor, and tumor necrosis factor-alpha by activated HIV-1-infected monocytes is attenuated by primary human astrocytes.

HIV-1-infected brain macrophages participate in neurologic dysfunction through their continual secretion of neurotoxins. We previously demonstrated that astroglial cells activate HIV-1-infected monocytes to produce such neurotoxic activities. In this study, the mechanism underlying these monocyte secretory activities was unraveled and found dependent on HIV-1's ability to prime monocytes for activation. LPS stimulation of HIV-1-infected monocytes resulted in an overexpression of eicosanoids, platelet-activating factor (PAF), and TNF-alpha. This was dependent on the level of HIV-1 infection and monocyte stimulation. Cell to cell interactions between activated virus-infected monocytes and primary human astrocytes reduced monocyte secretions. The capacity of astrocytes to deactivate monocytes was, notably, TGF-beta independent. Although astrocytes constitutively produced latent TGF-beta 2, HIV-1-infected monocytes neither affected TGF-beta 2 production nor converted it into a bioactive molecule. Furthermore, addition of rTGF-beta 1 or rTGF-beta 2 or its Abs to LPS-stimulated monocyte-astrocyte mixtures had no effect on monokine production. In contrast, addition of rIL-10 to LPS-stimulated monocytes produced a dose-dependent decrease in TNF-alpha. IL-10 mRNAs were detected in monocytes, but not astrocytes, following LPS treatment. These results suggest that macrophage activation, a major component of HIV-1 infection in the brain, precipitates neuronal injury by causing virus-infected cells to synthesize neurotoxins. The neurotoxins produced by monocytes are then regulated by astrocytes. Astrocytes therefore, can play either positive or negative roles for disease depending on prior macrophage activation. These findings begin to unravel the cellular control mechanisms that influence cognitive and motor dysfunctions in HIV-1-infected individuals.

Astrocytes↗
PubMed1993

Quantitation and kinetics of blood monocyte migration to acute inflammatory reactions, and IL-1 alpha, tumor necrosis factor-alpha, and IFN-gamma.

Monocytes migrate from the blood into acute inflammatory reactions, where they differentiate into macrophages, and after 12 to 24 h become the predominant histologic feature of the inflammatory infiltrate. The quantitation of monocyte migration into these reactions has been difficult. This report employs a novel combination of techniques to isolate highly purified monocytes from the blood of rats, and shows that these cells have a normal t1/2 of 26 h and migrate efficiently after i.v. injection into cutaneous acute inflammatory sites. Monocytes labeled with 51Cr accumulated in delayed-type hypersensitivity reactions, and sites injected with killed Escherichia coli, LPS, poly-inosine: cytosine, zymosan-activated serum (ZAS), a source of C5adesArg, and the cytokines IL-1 alpha, TNF-alpha, and IFN-gamma. Both radiolabeled monocytes and neutrophils migrated rapidly to E. coli, LPS, ZAS, IL-1 alpha, and TNF-alpha with a large increase in cell accumulation by 2 h. Neutrophil migration declined rapidly to undetectable levels by 3 to 4 h to all five stimuli, and monocyte migration to ZAS and IL-1 alpha also declined by this time. In contrast, E. coli, LPS, and TNF-alpha caused a sustained migration of monocytes for 5 to 6 h, long after neutrophils had stopped accumulating. Intradermal IFN-gamma did not recruit neutrophils but stimulated a prolonged monocyte migration from 1 to 6 h. Combinations of LPS, TNF-alpha, and IFN-gamma synergistically enhanced the late (> 5 h) but not the early phase of monocyte recruitment. In conclusion, purified monocytes isolated from rat blood can be used to quantify monocyte migration in vivo, and these cells migrate rapidly to cutaneous inflammation and in response to chemotactic factors, IL-1 alpha, TNF-alpha, and IFN-gamma, with initial kinetics similar to those of neutrophils. However, monocyte-selective mechanisms are induced by IFN-gamma and also appear to be involved in prolonged monocyte migration to TNF-alpha, LPS, and E. coli.

Acute Disease↗
PubMed1993

Cellular and cytokine dependent monocyte-mediated leukemic cell death: modulation by interferon-gamma and tumor necrosis factor-alpha.

Activated human monocytes and macrophages are involved in host defense against neoplastic cells. In view of cellular adoptive immunotherapy, we have studied the role of tumor necrosis factor-alpha (TNF-alpha) and gamma-interferon (IFN-gamma) in monocyte-mediated cytotoxicity on the level of both effector and leukemic target cells. Highly purified and IFN-gamma-activated monocytes were cytolytic to U937 cells up to 81.9 +/- 5.3% (mean +/- SEM) in a 24-hour MTT cytotoxicity assay at an effector-to-target-cell ratio of 10. Upon IFN-gamma activation these monocytes showed a 20-fold increase in TNF-alpha secretion of 663 +/- 122 pg/mL. Comparable concentrations of recombinant human TNF-alpha showed only cytostatic effects on U937 cells of approximately 20% after 24 hours, similar to the cytostatic effects of IFN-gamma-activated monocyte culture supernatants. These effects could be fully reversed by anti-TNF-alpha antibodies. U937 cells pretreated with TNF-alpha were almost completely resistant to monocyte-mediated cytotoxicity, supernatant-mediated cytostasis and to TNF-alpha up to 10(4) U/mL. IFN-gamma-activated monocytes were able to lyse TNF-alpha-modified U937 cells whereas IFN-gamma-activated monocyte supernatants showed only cytostatic activity after prolonged incubation. Additionally, target cell modulation by IFN-gamma potentiated the TNF-alpha-dependent cytolytic and cytostatic effects of monocytes, monocyte culture supernatants and TNF-alpha. We conclude that monocytes as a cellular component in monocyte-mediated cytotoxicity are far more potent in lysis of leukemic target cells than are secreted monokines. Furthermore, IFN-gamma and TNF-alpha are involved in the regulation of the susceptibility of leukemic cells for lysis by interactions with monocytes.

Antibodies↗
PubMed1996

HIV-1-Tat modulates the function of monocytes and alters their interactions with microvessel endothelial cells. A mechanism of HIV pathogenesis.

Monocytes are major targets of HIV infection in patients with AIDS. In vitro infection of monocytes with HIV is associated with increased expression of beta 2 integrins, which increases both monocyte aggregation and monocyte/endothelial adhesion as well as monocyte metalloproteinase (MMP-9) expression. Treatment of primary monocytes with soluble HIV-Tat protein mimicked many of the properties of HIV infection of monocytes. Tat treatment up-regulated the expression of the beta 2 integrins, which was associated with the formation of large aggregates of monocytes and increased adhesion to endothelial monolayers. Treatment of monocytes with Tat increased their adhesion to both untreated and TNF-alpha-treated endothelial monolayers, and adhesion was inhibited by inclusion of anti-beta 2 and anti-ICAM-1 Abs. The increased adhesion of activated monocytes was accompanied by substantial disruption of the endothelial monolayers, with retraction or detachment of individual endothelial cells. Tat treatment of monocytes up-regulated the synthesis and release of the protease MMP-9, providing a potential mechanism to explain endothelial cell/basement membrane detachment. Thus, extracellular Tat is capable of activating monocytes even in the absence of HIV infection. Our studies demonstrate that many of the effects of HIV infection on monocyte homotypic and heterotypic adhesion, protease secretion, and disruption of the endothelium can be mimicked by treatment with HIV-Tat protein alone. These results suggest a mechanism where monocytes could be inappropriately activated by HIV-Tat, secreted by HIV-infected cells, causing them to extravasate into underlying tissues and ultimately contribute to tissue damage as seen during the progression of AIDS.

Cell Adhesion↗
PubMed1997

Contact with T cells modulates monocyte IL-10 production: role of T cell membrane TNF-alpha.

IL-10, originally described as a cytokine synthesis inhibitory factor, is secreted by a number of cells of the immune system, including monocytes and T cells. IL-10 is a potent inhibitor of monocyte/macrophage activation, and we have shown previously this cytokine to be a major endogenous down-regulator of TNF-alpha in the rheumatoid joint. The mechanisms involved in regulating IL-10 production by cells of the monocyte/macrophage lineage are not yet clear, and most studies to date have used an exogenous triggering signal such as LPS. In this study, we have investigated the effects of cell-cell contact between human peripheral blood-derived activated T cells and monocytes in regulating monocyte IL-10 production. T cells, prestimulated with anti-CD3 mAb or with phorbol 12,13 di-butyrate and ionomycin, were fixed with glutaraldehyde and then incubated with monocytes. Fixed prestimulated T cells induced monocytes to secrete both IL-10 and TNF-alpha, and in addition, enhanced LPS-stimulated monocyte production of IL-10 and TNF-alpha in a dose-dependent manner. Stimulation of monocyte IL-10 production was abrogated when T cells were separated physically from monocytes within the tissue culture well. Using neutralizing Abs, we show that T cell contact-mediated induction of monocyte IL-10 is partially dependent on endogenous TNF-alpha and IL-1. Furthermore, T cell membrane TNF-alpha was shown to be one of the contact-mediated signals regulating monocyte IL-10 production. Endogenous IL-10 was shown to down-regulate T cell contact-mediated monocyte TNF-alpha production. Collectively, our results demonstrate that an autoregulatory loop exists involving both secreted and membrane-associated forms of IL-10 and TNF-alpha, and suggest that T cell-monocyte cognate interaction may play an important role in the regulation of monocyte cytokine production.

Cell Communication↗
PubMed1998

Regulation of monocyte interleukin-12 production by acute alcohol: a role for inhibition by interleukin-10.

Acute ethanol treatment results in decreased antigen presentation capacity (Th1-type immunity) and elevated interleukin IL-10 (Th2 cytokine) production in human monocytes. Monocytes can contribute to both Th1 (IL-12) and Th2 (IL-10) immune responses via production of IL-12 and IL-10, respectively. Thus, we tested the hypothesis that acute alcohol treatment might affect Th1/Th2 immune balance by altering monocyte production of IL-12 and IL-10. Neither acute ethanol treatment alone (25 to 100 mM) nor its combination with a bacterial challenge Staphylococcal enterotoxin B (SEB) induced IL-12 production in isolated blood monocytes. In contrast, the same physiological alcohol concentrations increased monocyte IL-10 levels, suggesting that ethanol can induce a dysbalance of monocyte-derived mediator production at the expense of Th1 cytokines. However, we found that monocyte activation with interferon-gamma (IFN-gamma) can prevent the preferential IL-10 induction by ethanol. IFN-gamma (100 units/ml) inhibited monocyte IL-10 production whether induced by 1 microg/ml of lipopolysaccharide (p < 0.01), 1 microg/ml of SEB (p < 0.02), or a combination of bacterial stimulation + ethanol (lipopolysaccharide: p < 0.01). Furthermore, decreased IL-10 was concomitant to an increase in IL-12 production in IFN-gamma-treated monocytes. Moreover, acute ethanol treatment augmented IL-12 production in IFN-gamma-treated monocytes in response to SEB stimulation (25 mM ethanol, p < 0.01; 100 mM ethanol, p < 0.01). Experiments with anti-IL-10 neutralizing antibody show that ethanol may prevent monocyte IL-12 induction via IL-10. These results suggest that inhibition of ethanol-induced IL-10 production by IFN-gamma treatment is permissive for IL-12 induction by alcohol stimulation in monocytes. Thus, our results imply that the presence or absence of IFN-gamma is critical in determining the effect of acute ethanol treatment on monocyte IL-12 versus IL-10 induction.

Adult↗
PubMed1998

Differential expression of the melatonin receptor in human monocytes.

Earlier studies have shown that the pineal hormone melatonin activates human monocytes. It is reported here that melatonin induces the secretion of IL-1, IL-6, and TNF in fresh and 1-day in vitro cultured monocytes that also express the melatonin receptor (Kd = 270 +/- 60 pM; 42,000-48,000 receptors/cell). However, when monocytes were cultured in vitro for 2 days, the number of receptors decreased to 11,000 receptors/cell, with the same Kd. LPS activation of fresh or 1-day cultured monocytes did not result in any increase in melatonin receptor number. LPS activation of 2-day cultured monocytes led to an increase in the number of melatonin receptors, from 11,000 receptors/cell to the plateau of 42,000 to 48,000 receptors/cell. The loss of receptors by 2-day cultured monocytes was not irreversible. Melatonin did not induce the release of IL-1, TNF, or IL-6 in monocytes cultured in vitro for 3 days and for up to 15 days, and these long time cultured monocytes did not express the melatonin receptors even after activation by LPS. The loss of melatonin receptors by monocytes cultured in vitro for 3 days and for up to 15 days was irreversible. Therefore, it is shown for the first time that human monocytes express melatonin receptors. Furthermore, human monocytes express melatonin receptors differentially depending on their state of maturation, and it appears that in vitro monocyte differentiation and maturation negatively affect human monocyte melatonin receptor expression.

Cell Differentiation↗
PubMed1998

Monocyte activation in platelet concentrates.

BACKGROUND AND OBJECTIVES: Cytokines in platelet concentrates contribute to febrile transfusion reactions. Activated monocytes are a major source of inflammatory cytokines, however the role of monocytes in cytokine production in platelet concentrates has not been clarified. This study undertook to quantitate monocytes, determine whether monocyte activation occurs and identify an association with IL-6 and IL-1beta concentrations in platelet concentrates. MATERIALS AND METHODS: 17 platelet concentrates were analysed for total leucocyte and monocyte counts, CD14 and CD16 monocyte-associated antigen expression and IL-1beta and IL-6 measurements on days 1, 2, 3, 4 and 5. RESULTS: Monocytes in all platelet concentrates expressed increased levels of CD14 and CD16 from day 1 of storage. 10/17 platelet concentrates had elevated IL-6 levels by day 3. Platelet concentrates with IL-6 levels above 15 pg/ml on day 5 had monocyte counts between 0.14 and 15.6 x 10(6)/unit on day 1, while those with IL-6 levels below 15 pg/ml had low monocyte counts of < 0.01 to 1.2 x 10(6)/unit on day 1. CONCLUSION: Monocytes present in platelet concentrates exhibit features of activation. Monocyte activation is present following the preparation of platelet concentrates, implicating the manufacturing process in its development. Increased IL-6 and IL-1beta levels during platelet concentrate storage are commonly associated with a higher monocyte count. However, no direct association could be identified between the extent of monocyte activation and the level of cytokine release.

Blood Platelets↗
PubMed1990

Detection of surface and cytoplasmic CD4 on blood monocytes from normal and HIV-1 infected individuals.

CD4 on blood monocytes is generally regarded as being found on a subset of blood monocytes. However, our results show that all monocytes are CD4+ but the number of molecules per cell is lower than T cells. We have performed immunofluorescent (flow cytometry, microscopy) analysis of monocytes from normal donors and HIV-1-infected patients using anti-CD4 (Leu-3a) and the monocyte-specific marker anti-CD14 (Leu-M3) monoclonal antibodies. Specifically: (1) 91% of monocytes from normal individuals show dual positivity for CD14 and CD4 (n = 14) as measured by flow cytometry; (2) 76% of monocytes expressed surface bound CD4 and CD14 when an enhanced two colour immunofluorescence microscopic technique was employed; (3) all CD14+ monocytes stained with an intensity of 3+(-)4+ for cytoplasmic CD4. Few monocytes were CD14- and CD4+. Cell surface CD4 expression was blocked with unconjugated anti-CD4 prior to staining; (4) the staining intensity for cytoplasmic CD4 in T cells was negligible; (5) CD4 expression on monocytes obtained from patients was as observed with normal individuals. The conclusion drawn is that all monocytes are CD4+ and the CD4 expression in monocytes is mainly cytoplasmic. Thus, all monocytes are potentially infectable with HIV-1.

Acquired Immunodeficiency Syndrome↗