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At least 19 recordsLinked to original sources
PubMed1988

Tumor necrosis factor and IL-1 associated with plasma membranes of activated human monocytes lyse monokine-sensitive but not monokine-resistant tumor cells whereas viable activated monocytes lyse both.

The purpose of our study was to determine some of the mechanisms involved in macrophage-mediated lysis of tumorigenic cells. A375 human melanoma cells (A375-R) resistant to lysis mediated by TNF and IL-1 were selected from the TNF- and IL-1-sensitive A375 parental melanoma cells subsequent to continuous (2 mo) exposure to rTNF. Peripheral blood monocytes isolated by centrifugal elutriation from healthy donors were incubated with rIFN-gamma and muramyl dipeptide, with a lipoprotein derived from Escherichia coli (CG-31362) or with LPS for 24 h. These activated monocytes lysed both the A375 (monokine-sensitive) and A375-R (monokine-resistant) melanoma cells. Activated tumoricidal macrophages fixed in 2% paraformaldehyde lysed only the TNF- and IL-1-sensitive A375 cells. These fixed monocytes contained both IL-1 and TNF activities as determined by D10 cell proliferation and L929 cytolysis assays, respectively. Nearly identical results were obtained with preparations of plasma membranes from activated human monocytes. Anti-IL-1 and/or anti-TNF sera neutralized the cytolysis of tumor cells mediated by free monokines, by fixed monocytes, or by plasma membrane preparations. In contrast, anti-TNF and/or anti-IL-1 sera did not inhibit tumor cell lysis by viable activated monocytes. We conclude that IL-1 and TNF molecules associated with the plasma membranes of activated monocytes mediate lysis of susceptible target cells. However, because activated monocytes lysed IL-1-and TNF-resistant target cells, molecules other than these monokines must also be involved in the antitumor activity of monocytes.

Cell Fractionation↗
PubMed1982

Production of T cell-activating monokine of guinea pig macrophages induced by MDP and partial characterization of the monokine.

The production of T cell-activating factor(s) by macrophages stimulated with muramyl dipeptide (MDP) was studied. By MDP stimulation, a rapid increase in intracellular activity of the T cell-activating factor was induced, which preceded an increase of the activity in the extracellular medium. The rapid appearance of the activity in the cell and that in the medium were both inhibited by cycloheximide or puromycin. These results demonstrated that MDP stimulated rapid production of T cell-activating factors by inducing de novo synthesis of the factors, and that these newly formed factors are rapidly secreted. The activities of intracellular and extracellular secreted factors were both found in high m.w. (50,000 to 90,000) and low m.w. (10,000 to 30,000) fractions by gel filtration. The secreted high m.w. factor migrated as a single peak and did not dissociate into smaller components in SDS-PAGE analysis, indicating that the high m.w. factor is neither a complex of low m.w. factor with other proteins nor an aggregate of low m.w. factors. The properties are similar to those of our previously reported factor that helped antigenic activation of T cells for lymphokine production.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Monokine-induced lung injury in rats: similarities to monocrotaline-induced pneumotoxicity.

Previous studies have shown that abnormal alveolar macrophages and biological activity resembling the macrophage-derived mediator interleukin-1 (IL-1) can be detected in bronchoalveolar lavage fluid from rats with monocrotaline-induced lung injury and pulmonary hypertension. To determine if monokines might play a pathogenic role in this model, the present study evaluated the effects of a murine monokine preparation enriched in IL-1 bioactivity on selected events characterizing the early pneumotoxic response to monocrotaline, including pulmonary edema and protein extravasation, pulmonary vascular hyperreactivity, and enhanced lung tissue activity of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC). Intravenous injection of the monokine preparation containing 200 units/kg IL-1 (quantified by lymphocyte activating factor assay) into intact rats produced pulmonary edema within 3 hr manifested by increases in the lung wet-to-dry weight ratio and in the extent of pulmonary albumin extravasation. The edema had resolved within 24 hr of monokine administration as indicated by a return to control levels of the wet-to-dry weight ratio and albumin extravasation index. The monokine preparation also increased the transfer of albumin across monolayers of cultured porcine pulmonary vascular endothelial cells. While salt solution-perfused rat lungs isolated from animals treated 3 hr previously with the monokine preparation were hyporesponsive to angiotensin II, preparations derived from animals treated 24 hr previously were markedly hyperresponsive to the vasoconstrictor actions of the peptide. Pressor responses to potassium chloride and prostaglandin F2a were unaffected by exposure to the monokine preparation. Lung ODC activity in monokine-exposed animals did not differ from control at 3, 6, or 24 hr after treatment. In contrast, a 24-hr exposure of cultured pulmonary vascular endothelial cells to the monokine preparation increased ODC activity approximately 100-fold. These observations indicate that a monokine preparation containing IL-1 bioactivity causes transient pulmonary edema and pulmonary vascular hyperreactivity and increases ODC activity in pulmonary vascular endothelial cells. Because the monokine preparation mimics certain aspects of monocrotaline-induced pneumotoxicity in the rat, it is reasonable to postulate that monokines could play a pathogenic role in this and similar animal models of lung injury and pulmonary hypertension.

Animals↗
PubMed1988

Glucose kinetics in rats infused with endotoxin-induced monokines or tumor necrosis factor.

This study was conducted to determine if macrophage elaborated monokines in general, and human recombinant tumor necrosis factor (hrTNF alpha) in particular alter glucose metabolism in a manner analogous to that observed in endotoxin-treated animals. Endotoxin-tolerant rats were infused for 3 hr with saline, E. coli endotoxin (100 micrograms/l weight) or monokines contained in conditioned media from endotoxin-stimulated RAW 264.7 cells (1 microgram/ml). Compared to saline- and endotoxin-infused rats, animals receiving the monokine mixture had no change in mean arterial blood pressure or heart rate but exhibited overt signs of morbidity including stupor and diarrhea. Monokine-infused rats remained euglycemic but had elevated lactate concentrations and a 15-30% increase in glucose rate of appearance (Ra). Nontolerant rats received a 3 hr infusion of saline, hrTNF alpha (15 micrograms/100 g), or heat-treated hrTNF alpha. HrTNF alpha infusion increased glucose Ra about 25% compared to the two control groups but did so without producing signs of morbidity seen in the monokine infused animals. Serum TNF levels were 6-fold higher in rats infused with the monokine mixture compared to animals infused with hrTNF alpha, and this reflected the different levels of TNF contained in the monokine mixture and hrTNF alpha infusates. Plasma insulin, glucagon, and catecholamine concentrations were increased in rats infused with either the monokine mixture or hrTNF alpha, but the increases were more pronounced in rats receiving the monokine mixture. The results demonstrate that monokines and hrTNF alpha increase glucose production in vivo, and that the effect may be mediated by endocrine changes known to influence glucose homeostasis.

Animals↗
PubMed1990

Role of monokines in control of anterior pituitary hormone release.

It has long been known that endogenous pyrogen, released as a result of injection of typhoid vaccine or in response to infection, produces fever and increases ACTH secretion. Recent studies have indicated that endogenous pyrogen is, at least in part, IL-1. This monokine has now been shown to activate the release of ACTH by a hypothalamic mechanism with release of CRF and possibly vasopressin, which stimulates the corticotrophs. There may also be a pituitary action to stimulate the release of ACTH directly. In our experiments we showed that IL-1 at low but not higher doses appears to act intrahypothalamically to stimulate GH and PRL release and to inhibit TSH release. In the meantime, another monokine, cachectin, was isolated and its structure determined. We have found that this monokine can act following its third ventricular injection to stimulate ACTH, PRL, and GH release and to inhibit TSH release, at least in part, by release of prostaglandins since indomethacin, an inhibitor of prostaglandin synthesis, produced a blockade of the responses except for those of ACTH. This peptide also has highly potent effects to alter pituitary hormone release by direct action on the pituitary to stimulate ACTH, GH, and TSH and to a slight extent PRL release. These actions appear to involve prostaglandins since indomethacin blocks all of the effects except for the effect on ACTH secretion. This monokine also produces a dose-related lowering of anterior pituitary cyclic AMP levels. When the monokine was incubated along with somatostatin, the lowering of cyclic AMP was reversed, and a potent PRL-releasing effect of the monokine was visible. We have begun studies with a third monokine, gamma interferon, which indicate that it stimulates ACTH release but suppresses plasma GH and TSH levels by a hypothalamic action. It is apparent that these various monokines have powerful effects to alter hypothalamic-pituitary function and that they probably mediate most of the effects of infections on the release of anterior pituitary hormones.

Animals↗
PubMed1983

T cell-activating monokines in guinea pigs: comparison of high and low molecular weight factors.

Guinea pig monokines produced by lipopolysaccharide-stimulated peritoneal macrophages were found in high (50,000-80,000) and low (10,000-30,000) molecular weight (m.w.) fractions by gel filtration. Both showed enhancing activity on the proliferative response of guinea pig and mouse thymocytes to PHA, but the high m.w. (65K) monokine was much more efficient than the low m.w. (15K) monokine in enhancing the response of lymph node T cells to PHA, suggesting its importance in the activation of peripheral T cells. The 65K monokine was coeluted with BSA present in the culture medium by DEAE-cellulose chromatography, but was clearly separated from it by hydroxylapatite chromatography. The immunoadsorption experiment with anti-BSA-coupled gel also indicated that 65K monokine is not a complex of low m.w. monokine with BSA. Our series of studies showed that most monokine activities were always found in the 65K fraction in guinea pigs. Thus, in guinea pigs, the 65K component appears to constitute a major class of T cell-activating monokines.

Animals↗
PubMed1989

Viral antigen stimulation of the production of human monokines capable of regulating HIV1 expression.

We have previously described model systems for cytokine-induced regulation of chronically HIV-infected promonocyte and T cell clones. Using these systems, we have shown that monokines contained in supernatants from LPS-stimulated human monocyte/macrophages (MO) up-regulate HIV expression, reflected by an increase in reverse transcriptase activity, viral RNA levels, and expressed viral proteins. Current studies were designed to determine whether viral Ag can interact with MO and secondarily affect HIV1 expression by stimulating monokine production. We found that certain herpes-group viruses, including CMV and EBV, augment HIV1 expression by inducing monokine production, whereas others, such as HSV1, HSV2, varicella-zoster virus, and human herpes virus 6 were unable to function in this capacity. The HSV1 and HSV2 Ag which failed to stimulate monokine production did not interfere with MO stimulation by CMV Ag, suggesting that failure to induce HIV expression was not attributable to MO suppression. When nonherpes group viruses were tested, we found that human adenovirus, hepatitis B virus, and vaccinia virus all failed to stimulate the production of monokines capable of activating HIV in the chronically infected cell lines. In contrast, HIV1 can augment its own expression by inducing the secretion of monokines which up-regulate HIV expression in the infected cells. The viral Ag-induced MO supernatants capable of up-regulating HIV expression did so in a dose-dependent manner, whereas viral Ag alone produced no significant change. Monokine production mediated by viral Ag was not attributable to contaminating endotoxin. These studies provide a model to determine whether other opportunistic infections may induce the expression of HIV by indirect mechanisms, such as the stimulation of cytokine production.

Acquired Immunodeficiency Syndrome↗
PubMed1994

[The role of monocytes in network mediated by both fibronectin and monokines in inflammation].

The effects of both fibronectin (FN) and monokines (IL-1 alpha, IL-6, TNF) on monocyte activation were studied. FN in the culture medium (200 micrograms/ml) induced strong monokine production that was mediated by the domain epitope including RGD sequence on FN and the VLA-5 integrins on monocytes. Each monokine or the combination of suboptimal dose of any monokines strongly induced FN production. These results indicate that monocytes activation in vitro may depend on not only monokines but on adhesion molecules such as FN-VLA-5. Peripheral blood monocytes from patients with systemic lupus erythematosus (SLE) demonstrated low responses to both fibronectin and monokines, while the plasma levels of FN in SLE patients elevated markedly compared with normal individuals (640 vs 285 micrograms/ml). Many studies have been reported that cytokines elevated in serum from SLE patients. These results indicated that maximally activated monocytes with both monokines and soluble FN in vivo in SLE patients could not be activated in vitro. Together with these results, FN play important roles in the cellular and humoral mechanisms of inflammation.

Fibronectins↗
PubMed1987

Effect of endotoxin-induced monokines on glucose metabolism in the muscle cell line L6.

Exposure of fully differentiated L6 myotubes to a crude monokine preparation from endotoxin-stimulated RAW 264.7 cells resulted in a rapid and substantial (70%) increase in fructose 2,6-bisphosphate concentration coincident with a depletion of cellular glycogen and an increased lactate production. During the time required for glycogen depletion (3 hr), stimulation of 3-O-methyl-D-glucose and 2-deoxy-D-glucose uptake was initiated and observed to reach a maximum enhancement of 200% 12-15 hr later. The monokine had no effect on the Km value for 2-deoxy-D-glucose uptake (1.1 mM), while Vmax was increased from 912 to 2400 pmol/min per mg of protein. The increase was cytochalasin B inhibitable and was dependent on protein synthesis. Photoaffinity labeling and equilibrium binding studies with [3H]cytochalasin B support the hypothesis that this increase in hexose transport was due to an increase in hexose transporters present in the plasma membrane. Purified recombinant interleukin-1 alpha had no effect on hexose transport, whereas purified recombinant cachetin/tumor necrosis factor did stimulate hexose uptake, with half-maximal stimulation occurring at 36 nM. Although cachetin accounts for most of the biological activity associated with the crude monokine preparations, it is not the only monokine capable of inducing glucose transport in L6 cells. Specific immunoabsorption of cachectin/tumor necrosis factor from the crude monokine preparation revealed a monokine that had a similar bioactivity at extremely low concentrations on L6 cells.

3-O-Methylglucose↗
PubMed1992

Modulation of endotoxin-induced monokine release in human monocytes by lipid A partial structures that inhibit binding of 125I-lipopolysaccharide.

We have previously shown that the synthetic tetraacyl precursor Ia (compound 406, LA-14-PP, or lipid IVa) was not able to induce the production of tumor necrosis factor, interleukin-1, and interleukin-6 in human monocytes but strongly antagonized lipopolysaccharide (LPS)-induced formation of these monokines. This inhibition was detectable at the level of mRNA production. To achieve a better understanding of molecular basis of this inhibition, we investigated whether lipid A precursor Ia (LA-14-PP), Escherichia coli-type lipid A (LA-15-PP), Chromobacterium violaceum-type lipid A (LA-22-PP), and synthetic lipid A partial structures and analogs (LA-23-PP, LA-24-PP, and PE-4) were able to influence the binding of 125I-LPS to human monocytes and compared this inhibitory activity with the agonistic and antagonistic action in the induction of monokines in human monocytes. 125I-LPS (20 ng per well) was added to human monocytes in the presence or absence of unlabeled rough Re mutant-derived LPS (Re-LPS) or lipid A compounds, and specific LPS binding was determined after 7 h. This binding was found to be dependent on CD14 as shown by the use of an anti-CD14 monoclonal antibody. Compound LA-14-PP was found to inhibit the binding of 125I-LPS to the cells in a similar dose-response to that of unlabeled LPS. This shows that the inhibitory capacity on LPS binding does not correlate with the monokine-inducing capacity because Re-LPS is active in inducing tumor necrosis factor, interleukin-1, and interleukin-6, while LA-14-PP is not. The strong capacity of LA-14-PP to inhibit 125I-LPS binding, however, correlates with the strong inhibitory capacity of this compound on LPS-induced monokine production. Compounds LA-15-PP, LA-23-PP, and LA-24-PP were active in the inhibition of 125I-LPS binding but were 5- to 10-fold weaker than Re-LPS and LA-14-PP. Of all lipid A structures tested, compound LA-22-PP expressed the weakest inhibitory capacity on LPS binding. These compounds showed again that the activity of binding inhibition does not correlate with the monokine-inducing capacity. We assume that the inhibitory effects of lipid A partial structures on LPS-induced monokine production have their origin in a competitive inhibition between LPS and the lipid A partial structures for the same binding site on the cell membrane.

Antigens, CD↗
PubMed1995

Glycosphingolipids from Sphingomonas paucimobilis induce monokine production in human mononuclear cells.

Glycosphingolipids (GSL) isolated from the gram-negative lipopolysaccharide (LPS)-free bacterium Sphingomonas paucimobilis have remarkable structural similarities with LPS and its hydrophobic part, termed lipid A. Like LPS, but in contrast to the structurally related ceramides and cerebrosides, GSL contain an alpha-linked, negatively charged pyranosidic glycosyl component adjacent to the lipid portion and are capable of forming membranes. Because of these similarities, it was of interest to investigate whether these GSL are also able to induce monokine production in human mononuclear cells (MNC). Our results show that a GSL containing four sugar residues (GSL-4A) induced the release of tumor necrosis factor, interleukin-6, and interleukin-1 in MNC, whereas GSL-1, containing only one glycosyl residue, was inactive. A minimal concentration of 1 microgram of GSL-4A per ml was necessary to induce monokine production in MNC, whereas LPS was as active at a 10,000-fold-lower concentration (0.1 ng/ml). Both GSL-4A-induced monokine production and LPS-induced monokine production were reduced by the bactericidal/permeability-increasing protein and GSL-1. In contrast to LPS, GSL-4A-induced monokine release could be inhibited neither by an anti-CD14 monoclonal antibody nor by lipid A partial structures. We therefore conclude that at the receptor level, different mechanisms are involved in the LPS- and GSL-4A-induced monokine release.

Antigens, CD↗
PubMed1989

Monokine regulation of glucose transporter mRNA in L6 myotubes.

Endotoxin-induced macrophage secretory proteins (monokines) have been shown to stimulate hexose uptake in L6 myotubes (1). In those studies a doubling of the Vmax for hexose uptake was observed which correlated with elevated numbers of glucose transporters (GT) in both plasma and microsomal membranes. To determine if these changes in transporter populations were due to increased GT mRNA, we performed Northern blot analysis using L6 cell RNA and a cDNA to the HepG2 glucose transporter. The L6 myotubes contained a single 2.8 kb species of GT mRNA that increased 2.5-fold after an 8h exposure to the monokine preparation. beta-Actin mRNA levels were unaltered by the treatment, indicating specificity of monokine action. Glucose transporter mRNA content appeared to reach a maximum 8 h after exposure to the monokine. Over the next 16 h the levels of this mRNA gradually decreased, approaching control levels. Data obtained from nuclear transcription run-on assays suggest that increased levels of CT mRNA are due to an increased rate of gene transcription. A second transporter, the insulin-sensitive glucose transporter, was also observed to be expressed in the L6 cells. Monokine treatment resulted in a 60% suppression of the mRNA coding for this protein.

Actins↗
PubMed1992

Effects of recombinant monokines on hepatic pyruvate dehydrogenase, pyruvate dehydrogenase kinase, lipogenesis de novo and plasma triacylglycerols. Abolition by prior fasting.

1. The effects of recombinant human tumour necrosis factor alpha (TNF) and murine interleukin-1 alpha (IL-1) on the activation state of the hepatic pyruvate dehydrogenase complex (PDHa), the activity of mitochondrial PDH kinase, hepatic lipogenesis de novo and plasma triacylglycerol (TG) concentrations were studied. 2. Monokine effects depended upon prior nutritional state. In rats fasted for 20 h or 45 h before monokine administration and refeeding (orally or with intravenous glucose), PDHa, TG and hepatic lipogenesis were not increased. In rats fed ad libitum, treatment with TNF plus IL-1 increased the contribution of hepatic lipogenesis to circulating TG to 550% of control values (P = 0.03) and plasma TG concentrations to 159% (P = 0.02), whereas PDHa increased slightly to 120% (P = 0.02) and liver glycogen content fell to 45.8% (P = 0.05) of control values. 3. Intrinsic hepatic PDH kinase activity was not changed by monokine treatment in rats fed ad libitum. 4. The increased lipogenesis de novo showed no correlation (r2 = 0.05, not significant) with hepatic PDHa in individual animals fed ad libitum. 5. In conclusion, these results suggest that monokines increase pyruvate flux through hepatic PDH in vivo in rats fed ad libitum primarily by mechanisms other than covalent modification of PDH. Prior nutritional status exerts a permissive effect for monokine stimulation of PDHa and lipogenesis, consistent with a substrate-mediated action, but the mechanism of this permissive effect remains uncertain.

Animals↗
PubMed2001

Production of monokines in patients under polysulphone haemodiafiltration is influenced by the ultrafiltration flow rate.

BACKGROUND: Chronic haemodialysis patients show various clinical signs of immunodeficiency and there is growing evidence that a dysregulated monocyte cytokine production is heavily involved in this deficiency. The production of monokines in vitro has been proposed to correlate closely with the in vivo immune status and to be of high clinical relevance in cuprophane haemodialysis. Even though it is well known that the biocompatibility of dialyser membranes has a significant impact on immune functions, little is known about the influence of the ultrafiltration flow rate (UFR). The aim of this study was to investigate the potential long-term effects of UFR on the production of interleukin-10 (IL-10), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in an intra-individual study design. METHODS: In 11 patients previously treated with polysulphone haemodiafiltration, UFR was reduced from 40-46 ml/min to 24-28 ml/min, then to 7-10 ml/min before it was reinstated at 40-46 ml/min for periods of 4 weeks each. Monokine secretion into culture supernatants and mRNA expression (assessed using a novel Taqman PCR technique), were determined in a whole blood assay after lipopolysaccharide stimulation. RESULTS: Reduction of UFR led to a significant increase in IL-10 secretion and mRNA expression (P=0.012, P=0.001). Conversely, a substantial (but not complete) decrease was observed when UFR returned to initial levels. In contrast, supernatant concentrations of IL-1beta (P=0.04) and IL-6 (P=0.003), and mRNA expression of both monokines (P<0.001, P<0.001) decreased significantly when UFR was reduced. Calculation of the IL-1beta/IL-10 ratio also revealed a decrease when UFR was reduced, with an increase again being observed when the initial degree of UFR was reinstated (P<0.001). CONCLUSIONS: These results indicate a significant impact of UFR on the production of monokines at both the transcriptional and the protein level. We suggest that middle molecule removal has to be considered as a possible pathophysiological mechanism to explain our findings. Since monokine production in vitro was shown to be closely correlated with the in vivo immune status in patients on cuprophane haemodialysis, further investigations are necessary to clarify the impact of UFR on the immunocompetence of patients under polysulphone haemodiafiltration.

Adult↗
PubMed1995

Interaction of the cell-binding domain of fibronectin with VLA-5 integrin induces monokine production in cultured human monocytes.

The effect of fibronectin on IL-1 alpha, IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), and IL-6 production was investigated with cultured monocytes isolated from human peripheral blood. Monokine concentrations were determined by both ELISA and bioassay. Fibronectin markedly stimulated the secretion of IL-1 alpha, IL-1 beta, TNF-alpha and IL-6 from cultured monocytes in a dose-dependent manner, with the maximal effect apparent within 24 h. Northern blot analysis revealed a marked increase in the abundance of mRNA specific for each monokine on exposure of monocytes to fibronectin. Monoclonal antibodies to the alpha chain of very late antigen (VLA)-5, the beta 1 integrin, the alpha chain of Mac-1, and the beta 2 integrin, as well as the synthetic peptide of GRGDSP (which corresponds to the cell-binding domain of fibronectin), inhibited (> 50%) fibronectin-induced monokine production. Monoclonal antibodies to the alpha chain of VLA-4, and the alpha chain of LFA-1, as well as the synthetic peptide CS-1 (which corresponds to the alternatively spliced connecting segment of fibronectin) and the control peptide GRADSP, had no inhibitory effect on monokine production. A MoAb, R60, that recognizes an epitope of the fibronectin molecule that includes the RGD sequence, inhibited monokine production, whereas the MoAb Y16, which recognizes another epitope of fibronectin not including RGD, did not. These results indicate that fibronectin-induced production of IL-1 alpha, IL-1 beta, TNF-alpha and IL-6 from cultured monocytes is mediated predominantly by interaction of the cell-binding domain of fibronectin with VLA-5, although Mac-1 also may contribute to this effect of fibronectin. Our results indicate that the interaction of fibronectin with integrins may contribute to the cytokine network in inflammatory response.

Binding Sites↗
PubMed1994

Monokine-mediated increase in human immunodeficiency virus type 1 expression in chronically infected promonocyte- and T-cell-derived lines.

The ACH-2 cell clone derived from a human T-cell line and chronically infected with human immunodeficiency virus 1 (HIV-1) and the U1 cell clone derived from a human promonocyte cell line and also chronically infected with HIV-1 produce HIV-1 in a response to stimulation with monokine-enriched supernatants prepared from highly purified populations of peripheral blood-derived human monocytes. Monokine-mediated expression of HIV-1 in these cell lines resulted in augmented virus production reflected by increases in reverse transcriptase (RT) activity, production of p24 antigen, and synthesis of major viral proteins. Examination of the cells by electron microscopy revealed numerous HIV-1 virions in the cells treated with the supernatants. This stimulation of virus production by monokine-enriched supernatants resulted in approximately 100-fold increases in RT activity and p24 antigen expression in comparison with those in untreated U1 and ACH-2 cells. Absorption of monokine-enriched supernatants with rabbit anti-tumor necrosis factor alpha antibody removed most, but not all, of the induced HIV-1 RT activity and p24 antigen expression in U1 and ACH-2 cell lines, suggesting that tumor necrosis factor alpha in the monokine-enriched supernatants is a major factor in the induction of HIV-1 expression in these cells.

Adult↗
PubMed1996

Biochemical characterization and protein kinase C dependency of monokine-inducing activities of Toxoplasma gondii.

Previous reports have indicated that the early induction of interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-alpha), IL-1beta, and IL-10 is crucial for the establishment and regulation of host cell-mediated immunity to the intracellular protozoan parasite Toxoplasma gondii. In this study, we demonstrate that a soluble tachyzoite extract (soluble tachyzoite antigen) can trigger the expression of these four monokines by murine inflammatory macrophages. Further characterization revealed that the parasite molecules in soluble tachyzoite antigen responsible for monokine induction are heat stable at 100 degree C but differ in sensitivity to protease digestion. Thus, the tachyzoite factors that stimulate TNF-alpha and IL-to expression were found to be more resistant to treatment with proteinase K than those responsible for IL-12 and IL-10 induction. Similarly, while the factors responsible for the induction of all four monokines were found to be sensitive to periodate oxidation, the TNF-alpha-stimulating activity was partially resistant to treatment with the compound at a low concentration (1 mM). A further dichotomy in monokine induction signals was inferred from experiments with isoquinoline sulfonamide protein kinase inhibitors. The latter work suggested that the pathways for TNF-alpha and IL-1beta are protein kinase C dependent, while expression of IL-12 and expression of IL-10 share distinct signal transduction mechanisms involving other kinases. Together, these data argue that monokine induction by T. gondii is mediated by glycoproteins that may belong to distinct groups in terms of their biochemical properties and intracellular signaling pathways.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗