Functional Activity Of Monocytes Research Articles

Effect of a pyrimidine derivative on the level of cytokines in conditions of streptococcal wound infection

Diseases caused by Streptococcus pyogenes are one of the significant problems of practical health care, due to the ability of this pathogen to cause morbidity in all age groups of the population with the development of different complications. The streptococcal infection is accompanied, along with infectious and inflammatory symptoms, by a pronounced immune response to Streptococcus pyogenes, which is mediated by the functional activity of monocytes and dendritic cells responsible for the production of pro- and anti-inflammatory cytokines that regulate the interaction, proliferation and functional activity of all participants in the cellular and humoral links of immunity. The purpose is to study the effect of a pyrimidine derivative on the level of pro- (IL-1β, IL-6, IL-8) and anti-inflammatory interleukins (IL-4, IL-10) in conditions of experimental streptococcal wound infection. The study of the effect of the pyrimidine derivative 3-[2-[(4,6-dimethylpyrimidin-2-yl) amino]-2-oxoethyl]quinazolin-4(3H)-one was carried out in vivo on the model streptococcal wound infection. The experiments were carried out on CBA mice 3 months old (20-22 g). Animals were divided into groups: control I–healthy animals, which were injected with water for injection; control II–infected untreated animals; experience I – animals that were treated intraperitoneally with a pyrimidine derivative at a dose of 36 mg/kg for 7 days, starting from the first day of infection; experiment II – animals that were treated intraperitoneally with the reference drug cefepime at an average therapeutic dose of 50 mg/kg in the same regimen as the test compound. The levels of pro- and anti-inflammatory interleukins in blood serum were determined by enzyme immunoassay. The study found that the pyrimidine derivative 3-[2-[(4,6-dimethylpyrimidin-2-yl)amino]-2-oxoethyl]quinazolin-4(3H)-one under conditions of streptococcal wound infection has an immunoregulatory effect, manifested in a decrease in pro-inflammatory and an increase in anti-inflammatory interleukins.

The Role of miRNA in Regulating the Fate of Monocytes in Health and Cancer.

Monocytes represent a heterogeneous population of blood cells that provide a link between innate and adaptive immunity. The unique potential of monocytes as both precursors (e.g., of macrophages) and effector cells (as phagocytes or cytotoxic cells) makes them an interesting research and therapeutic target. At the site of a tumor, monocytes/macrophages constitute a major population of infiltrating leukocytes and, depending on the type of tumor, may play a dual role as either a bad or good indicator for cancer recovery. The functional activity of monocytes and macrophages derived from them is tightly regulated at the transcriptional and post-transcriptional level. This review summarizes the current understanding of the role of small regulatory miRNA in monocyte formation, maturation and function in health and cancer development. Additionally, signatures of miRNA-based monocyte subsets and the influence of exogenous miRNA generated in the tumor environment on the function of monocytes are discussed.

The estimation of intensity of inflammatory alterations of blood in early postinfarction remodeling

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Structural postinfarction abnormalities is connected with inflammation. For better understanding of pathogenesis of postinfarction remodeling, it was studied the intensity of inflammatory disorders in early postinfarction period. Purpose Research of the intensity of inflammatory response in early postinfarction remodeling. Materials and methods 772 of patients with myocardial infarction (MI) were examined. Clinical blood analysis was performed at admission and on the 5th day of MI, as well as immunological examination, Echocardiography. Results In patients with end-diastolic diameter (EDD) of left ventricle (LV) ≥ 55 mm, 5 day MI white blood cells (WBC) level (8,0 ±2,1*109/l vs 7,3 ± 1,9*109/l, p = 0,0001), absolute number of neutrophils (5,0 ± 1,7* 109/l vs 4,5 ± 1,4*109/l, p = 0,0006) and monocytes (0,64 ± 0,30*109/l vs 0,57 ± 0,30*109/l, p = 0,005) were higher compared patients with EDD ≤ 55 mm. The inflammatory alterations in patients with increased end-diastolic volume (EDV) and end-systolic volume (ESV) of left ventricle was similar. The LV EDD was correlated with WBC level (r = 0,3; p = 0,00002), also with absolute number of neutrophils (r = 0,3; p = 0,0002) and monocytes (r = 0,3; p = 0,007). The positive connection of EDV LF with level of WBC (r = 0,3; P = 0,007) and absolute number of neutrophils (r = 0,3; p = 0,0002) was revealed. The positive connection of ESV LV with absolute number of neutrophils (r = 0,3, р=0,04; accordingly). It should be noted that increase of ESD LV more 37mm was not accompanied by authentic increase of inflammatory factors, but the connection of ESV LV with Il-6 was noted (ρ=0,3; р=0,03). As far as contractive function of myocardium declined, it was registered the increase of neutrophils (neutrophils on the 5 day in EF 55% and more - 4,5 ± 1,4*109/l, EF 55-40% - 4,8 ± 1,5*109/l, EF less 40% - 5,1 ± 2,1*109/l, p = 0,002), also in formation of areas of akinesia (neutrophils on the 1 days - 9,2 ± 3,3*109/l vs 8,3 ± 3,1*109/l, р=0,05) and aneurysm of LV (5,08 ± 1,71*109/l vs 4,52 ± 1,48*109/l, р=0,0006). It should be noticed that functional activity of monocytes in patients with aneurism of LV was lower than in patients without aneurism (CD14 0,035 ± 0,02*109/l vs 0,049 ± 0,02*109/l, р=0,05). It appears important obtained data that with hypertrophy LV and diastolic disfunction was noticed authentic increase of lymphocytes, expressing the marker of apoptosis CD95 (0,458 ± 0,276*109/l vs 0,335 ± 0,155*109/l, р=0,05; 0,441 ± 0,26*109/l vs 0,342 ± 0,21*109/л, р=0,01, accordingly). Conclusion The increased activity of inflammatory markers, decline of functional activity of monocytes, the elevation of apoptosis marker, associated with bigger intensity of postinfarction remodeling processes. The acute phase of inflammation is necessary stage of healing, but with long-term clinical case, excessive activation or alteration of functional activity of leukocytes can lead to growth of structural and electrical remodeling.

Нарушение врожденного иммунитета и выраженности иммунокомплексных реакций у беременных с невынашиванием на фоне экстрагенитальной патологии

Изучены функциональная активность моноцитов и концентрация циркулирующих иммунных комплексов в кровибеременных с хронической патологией печени и репродуктивными потерями на раннем сроке в анамнезе. У беремен-ных в первом триместре гестации при неблагоприятном преморбидном фоне выявлено снижение показателей фагоци-тарной активности моноцитов, что свидетельствует о снижении функциональной способности макрофагов будущейматери. Наряду с недостаточностью неспецифической резистентности организма у обследованных пациенток отмеча-лось повышение циркулирующих иммунных комплексов за счет патогенных среднемолекулярных фракций. Наиболеенизкие показатели фагоцитарной активности моноцитов и существенное повышение концентрации циркулирующихиммунных комплексов выявлены у пациенток с обострением неалкогольного стеатогепатита, что могло спровоциро-вать преждевременное прерывание беременности в первом триместре.

OXYGEN-DEPENDENT PHAGOCYTOSIS OF BLOOD MONOCYTES IN CHILDREN WITH HELICOBACTER PYLORI-ASSOCIATED GASTRIC AND DUODENAL EROSIONS AND ULCER

The aim of the research is to study oxygen-dependent phagocytosis of blood monocytes in children with gastric and duodenal erosions and ulcers by chemiluminescence analysis. The subjects of the research were blood monocytes, extracted from blood in 44 children with gastric and duodenal erosions and ulcers in the ages from 11 to 18 years. Microscopic tests for the bioptats of gastric mucosa of both standard regions and edges of ulcer defects had resulted in the determination of 2 groups of the patients with gastric and duodenal erosions and ulcers. The 1st group was represented by Helicobacter pylori high dissemination. As for the 2nd group, the patients showed low bacterization. The tests for luminol-dependent hemiluminescence of blood monocytes in patients with H. pylorihigh dissemination of gastric and duodenal mucosa demonstrated the significant increase of the intensity and the growth of areas both under the curve of spontaneous response and under the curve in the zimozan-induced process as compared to the monocyte activity in the group with low dissemination. Following the lucigenin- dependent chemiluminescence reactions in the group with H. pylori high dissemination we had found significant increase of the time of approaching the peak in both spontaneous response and zimozan- induced processes while the activation index was higher in comparison with phagocyte activities of monocytes in the group with low dissemination. Further stage of the research was to identify CagA-positive strains of H. pylori in the children with gastric and duodenal erosions and ulcers. Studying chemiluminescence activity of blood lymphocytes in the patients with anti-CagA antibodies we found the true increase of the time of reaching the peak, the intensity and the area under the curve in spontaneous process in luminol-dependent response and the time of reaching intensity peak and the intensity of spontaneous chemiluminescence reaction, lucigenin being an activator. So we marked the increase of the activity of oxygen-dependent phagocytosis of blood monocytes in children with H. pylori associated with gastric and duodenal erosions and ulcers related to H. pylori increased bacterization. The growth of H. pylori dissemination results in the higher stage of stomach mucosa inflammation. Therefore active phagocytes generate more intensively the formation of active forms of oxygen, free radicals and the products of peroxide oxidation. CagA-positive strains of H. pylori, as a rule, are associated with the higher level of inflammatory activity than CagA-negative ones. As a result of such influence the functional activity of monocytes increases, because they are «professional » phagocytes. The ability to perform phagocytosis is better expressed in them as compared to other leukocytes.

Monocytes of patients with unstable angina express high levels of chemokine and pattern-recognition receptors

Background and aimsMacrophages derived from monocytes play an important role in atherosclerosis progression. Subpopulations of circulating classical, intermediate, and non-classical monocytes possess distinct functions and phenotypes, and participate in the pathogenesis of disease. The aim of this study was to compare the quantity and phenotypes of circulating monocyte subpopulations in patients with established atherosclerosis and healthy control individuals. Additionally, the study aimed to provide insight into the functional activity of monocytes against a heat shock protein (HSP60). MethodsChemokine and pattern recognition receptors in monocyte subsets obtained from peripheral blood of acute and chronic coronary artery disease patients and controls were quantified by flow cytometry. Furthermore, monocytes from healthy controls were stimulated in vitro with HSP60, and the cytokines produced by them were evaluated by flow cytometry. ResultsEighteen controls (C), 34 individuals with risk factors for cardiovascular disease (RF), 32 patients with stable angina (SA), and 16 patients with unstable angina (UA) were enrolled in the study. The absolute count of intermediate monocytes was found to be increased in patients of the UA group; high frequencies of the chemokine receptors CCR2, CCR5, and CX3CR1 were also observed in this subpopulation. Moreover, the pattern recognition receptors TLR2 and TLR4 were more frequent in intermediate monocytes from the UA group. Furthermore, the intermediate monocytes from healthy individuals produced IL-12p70 after stimulation with HSP60. ConclusionsOur results show that intermediate monocytes of UA patients exhibited an enhanced expression of the receptors involved in the recognition of damage-associated molecular patterns (DAMPs) and enhancement of the migratory function. Hence, they might contribute to the propagation and progression of inflammation observed in atherosclerosis, especially in the acute setting.

Functional Activity of Monocytes and Macrophages in HTLV-1 Infected Subjects

The Human T lymphotropic virus type-1 (HTLV-1) infects predominantly T cells, inducing proliferation and lymphocyte activation. Additionally, HTLV-1 infected subjects are more susceptible to other infections caused by other intracellular agents. Monocytes/macrophages are important cells in the defense against intracellular pathogens. Our aims were to determine the frequency of monocytes subsets, expression of co-stimulatory molecules in these cells and to evaluate microbicidal ability and cytokine and chemokine production by macrophages from HTLV-1 infected subjects. Participants were 23 HTLV-1 carriers (HC), 22 HAM/TSP patients and 22 healthy subjects (HS) not infected with HTLV-1. The frequencies of monocyte subsets and expression of co-stimulatory molecules were determined by flow cytometry. Macrophages were infected with L. braziliensis or stimulated with LPS. Microbicidal activity of macrophages was determined by optic microscopy. Cytokines/chemokines from macrophage supernatants were measured by ELISA. HAM/TSP patients showed an increase frequency of intermediate monocytes, but expression of co-stimulatory molecules was similar between the groups. Macrophages from HTLV-1 infected individuals were infected with L. braziliensis at the same ratio than macrophages from HS, and all the groups had the same ability to kill Leishmania parasites. However, macrophages from HTLV-1 infected subjects produced more CXCL9 and CCL5, and less IL-10 than cells from HS. While there was no correlation between IFN-γ and cytokine/chemokine production by macrophages, there was a correlation between proviral load and TNF and CXCL10. These data showed a dissociation between the inflammatory response and microbicidal ability of macrophages from HTLV-1 infected subjects. While macrophages ability to kill an intracellular pathogen did not differ among HTLV-1 infected subjects, these cells secreted high amount of chemokines even in unstimulated cultures. Moreover the increasing inflammatory activity of macrophages was similar in HAM/TSP patients and HC and it was related to HTLV-1 proviral load rather than the high IFN-γ production observed in these subjects.

Regulatory Effect of Cinnamaldehyde on Monocyte/Macrophage-Mediated Inflammatory Responses

Cinnamaldehyde (CA) has been known to exhibit anti-inflammatory and anticancer effects. Although numerous pharmacological effects have been demonstrated, regulatory effect of CA on the functional activation of monocytes and macrophages has not been fully elucidated yet. To evaluate its monocyte/macrophage-mediated immune responses, macrophages activated by lipopolysaccharide (LPS), and monocytes treated with proaggregative antibodies, and extracellular matrix protein fibronectin were employed. CA was able to suppress both the production of nitric oxide (NO) and upregulation of surface levels of costimulatory molecules (CD80 and CD69) and pattern recognition receptors (toll-like receptor 2 (TLR2) and complement receptor (CR3)). In addition, CA also blocked cell-cell adhesion induced by the activation of CD29 and CD43 but not cell-fibronectin adhesion. Immunoblotting analysis suggested that CA inhibition was due to the inhibition of phosphoinositide-3-kinase (PI3K) and phosphoinositide-dependent kinase (PDK)1 as well as nuclear factor-(NF-) κB activation. In particular, thiol compounds with sulphydryl group, L-cysteine and dithiothreitol (DTT), strongly abrogated CA-mediated NO production and NF-κB activation. Therefore, our results suggest that CA can act as a strong regulator of monocyte/macrophage-mediated immune responses by thiolation of target cysteine residues in PI3K or PDK1.

Blood monocytes of untreated asthmatics exhibit some features of tissue macrophages.

Airway macrophages are activated in asthmatic subjects. Peripheral blood monocytes from these subjects present some functional features of activation, but their membrane markers are not known. Recently a new subtype of blood monocytes, CD14+/CD16+, has been identified which possesses the characteristics of tissue macrophages. A study was carried out on nine normal subjects and 11 untreated asthmatics having variable severities of the disease to examine the phenotypic characteristics of monocytes. CD14, CD16, HLA-DR, CD11a, CD11b, CD44 and CD54 were studied using double fluorescence flow cytometry since these antigens have been defined in the CD14+/CD16+ monocytes. The functional activation of monocytes was examined using the release of superoxide anion. The co-expression of CD14 and CD16 by monocytes in terms of percentage and mean fluorescence intensity was significantly higher in asthmatics (P < 0.002 and P < 0.0001, respectively, Mann-Whitney U-test). There was no difference for the other membrane markers between asthmatics and normal subjects. Superoxide anion release was significantly increased in asthmatic subjects (P < 0.01). This study shows that most blood monocytes of asthmatics are CD14+/CD16+ and are likely to present features of tissue macrophages.

Is there an association between angiotensin-converting enzyme gene polymorphism and functional activation of monocytes and macrophage in young patients with essential hypertension?

This study was undertaken to determine whether the phenotype of monocytes and monocyte-derived macrophages is more proatherogenic in young persons with arterial hypertension and whether this phenotype is affected by smoking or polymorphism of the angiotensin-converting enzyme (ACE) gene. We enrolled 40 young patients (24.1 +/- 4.7 years) with previously untreated arterial hypertension and 40 age-matched healthy controls. There were 20 smokers and 20 non-smokers in each group. In the hypertensive group, we found enhanced monocyte expression of CD11a (P < 0.001), reduced expression of CD49d (P < 0.001) and CD62L (P < 0.005), greater oxidative stress in resting and phorbol-12-mistrate-13-acetate-stimulated monocytes (P < 0.001), enhanced adhesion of monocytes to endothelial cells (P < 0.001), greater expression of CD36 on monocyte-derived macrophages (P < 0.001), and enhanced production of reactive oxygen species by resting and phorbol-12-mistrate-13-acetate-stimulated macrophages (P < 0.001). Cigarette smoking by hypertensive patients was associated with enhanced (P < 0.002) CD11a expression. There were no associations of ACE gene polymorphism with cellular expression or reactive oxygen species production studied among hypertensive patients. Only CD62L expression in DD homozygote participants was higher (P < 0.039) than in II homozygote participants. It is concluded that arterial hypertension affects the function of monocytes/macrophages in young persons. Polymorphism of the ACE gene is without effect on the functional activation of monocytes and macrophages.

Role of toll-like proteins in the realization of effects of chorionic gonadotropin on the functional activity of monocytes

Chorionic gonadotropin (CG) is the key pregnancyhormone. It is known that the main immunomodulatingeffects of CG are exerted in the presence of monocytesand/or macrophages [1], on the surface of which spe-cific hormone receptors (LH/CG-Rs) are expressed [2].The extracellular domain of LH/CG-R contains numer-ous leucine-rich repeats, which form homologous siteswith Toll-like receptors (TLRs) [3]. TLRs are classifiedinto the family of leucine-rich proteins and interactwith both the hydrophobic and hydrophilic surfaces ofreceptor molecules through amphipathic loops formedby multiply repeated structures [4]. One of expressedTLR isoforms, TLR4, is widely spread in monocytes; itis involved in the binding of lipopolysaccharides(LPSs) of gram-negative bacteria. During pregnancy,monocytes actively infiltrate decidual tissue in the con-tact zone with invasive trophoblast [5], phagocytizingcellular detritus and apoptotic bodies [6] and secretinglarge amounts of biologically active compounds [7].The goal of this study was to investigate the effectsof CG on the functional activity of woman’s monocytesand to determine the role of Toll-like proteins as possi-ble receptor molecules for the pregnancy hormone.This study was performed with an enriched popula-tion of peripheral blood monocytes of seven (n = 7)healthy fertile women at the follicular stage of the men-strual cycle. Mononuclear cells were isolated formvenous blood by centrifugation in a ficoll–verografindensity gradient (1.077 g/cm

Defective activity of monocytes from patients with non-Hodgkin lymphoma

Mononuclear phagocytic function is not well defined in non-Hodgkin lymphoma patients although, defective function of those cells has been reported in patients with Hodgkin disease and other solid tumors. The potential application of granulocyte-macrophage-colony stimulating factor (GM-CSF) in the prevention and treatment of infections in those patients is being studied. Phagocytosis and microbiocidal activity of monocytes in peripheral blood from 10 newly diagnosed patients and 14 healthy donors were tested cytologically against a strain of Candida albicans, and chemotaxis was evaluated in a Boyden chamber using zymosan-activated serum as a chemotactic agent. Cells were assayed under basal conditions and after incubation with GM-CSF (12 ng/mL). The phagocytosis and chemotactic activity of monocytes from non-Hodgkin lymphoma patients was lower than results obtained with cells from healthy donors (P < 0.05), and microbiocidal activity against Candida albicanswas similar in both groups. After exposure to GM-CSF, the functional activity of monocytes from control donors was only slightly modified (P > 0.05); by contrast, the percentage of mononuclear phagocytic cells in non-Hodgkin lymphoma (NHL) patients increased from 41 +/- 3% to 53 +/- 3%, the phagocytic index from 0.6 +/- 0.1 to 0.87 +/- 0.1 (P < 0.05), microbiocidal activity against Candida from 54 +/- 5% to 66 +/- 6% (P > 0.05), and chemotaxis from 43 +/- 8 cells per field to 48 +/- 9 cells per field (P > 0.05). The results of this study indicate that there is defective phagocytic and chemotactic activity in monocytes from NHL patients at diagnosis. "In vitro" improvement of phagocytic activity was observed after exposure to GM-CSF.

Decreased Macrophage Colony-Stimulating Factor mRNA Expression From Activated Cord Versus Adult Mononuclear Cells: Altered Posttranscriptional Stability

We have previously shown that protein production and mRNA expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and interleukin-3 are decreased in stimulated mononuclear cells (MNCs) from human umbilical cord compared with adult peripheral blood. These deficiencies may contribute to the increased susceptibility of neonates to infection. Macrophage colony-stimulating factor (M-CSF) regulates the proliferation, differentiation, and functional activation of monocytes. In the present study, we compared the regulation of M-CSF gene expression and protein production from stimulated cord and adult MNCs. Upon adhesion to tissue culture flasks, both cord and adult MNCs constitutively expressed M-CSF mRNA. In response to both adhesion and recombinant human GM-CSF (rhGM-CSF) stimulation for 120 hours, radioimmunoassays and bioassays showed that cord MNCs produced twofold to threefold less M-CSF protein compared with adult MNCs. Northern blot analysis also showed a fourfold decrease in M-CSF mRNA expression in both unstimulated and GM-CSF-induced cord versus adult MNCs. M-CSF mRNA expression in both cord and adult MNCs peaked between 16 and 24 hours and decreased to normal levels by 48 hours. We next determined the relative rates of transcription of the M-CSF gene by nuclear run-on assays in both cord and adult MNCs. The basal level signal of the M-CSF gene was similar between cord and adult MNCs. The transcriptional rate after stimulation with rhGM-CSF appeared to increase to a similar extent in both cord and adult MNCs (130% +/- 10% v 150% +/- 15%, C v A, n = 3, mean +/- SD). The comparative stability of M-CSF mRNA from cord versus adult MNCs was next determined by actinomycin D decay studies. The half-life of M-CSF mRNA from stimulated adult MNCs was 70 +/- 7.0 minutes (n = 4) compared with 47 +/- 2.8 minutes (n = 3) from stimulated cord MNCs (mean +/- SD, P < .05). To further determine the involvement of labile protein factors in posttranscriptional regulation, cord and adult MNCs were incubated with cycloheximide (CHX; 10 micrograms/mL). There was a significant increase in the induction of M-CSF mRNA by CHX treatment in both cord and adult MNCs. The increase of M-CSF mRNA induction by CHX was 2.5 times higher in cord MNCs compared with that in adult MNCs. These results suggest that there are one or more labile proteins that regulate M-CSF transcript stability in both cord and adult MNCs.(ABSTRACT TRUNCATED AT 400 WORDS)

Phenotypic and functional activation of monocytes in HIV-1 infection: interactions with neural cells

To investigate mechanisms that facilitate transendothelial migration of HIV-infected leukocytes and their interactions with neural tissues early in the disease, we studied peripheral blood from Centers for Disease Control class A patients. Patients' monocytes displayed increased quantities of the adhesion molecules CD11a, CD11b, and very late antigen 4 (VLA-4). Expression of these correlated directly with the numbers of monocytes that migrated through confluent endothelium. These ligands also mediated leukocyte interactions with cultured human neural cell lines. Although patients' cells bound in greater numbers, there was no evidence of target cell injury. To evaluate the direct effect of HIV-1 on monocyte neuroadhesion, we compared infected with uninfected monocytoid (U-937,THP-1) and T lymphoblastoid (MT-4) cell lines. HIV infection increased the neuroadhesiveness of monocytoid lines only. By using lines with more than 95% HIV-infected cells, we demonstrated that HIV-1 gp120 participates with lymphocyte function-associated antigen 1 and VLA-4 to mediate monocyte-neural cell interactions.

Defensin of human neutrophils modulates the functional activity of monocytes

Defensin of human neutrophils modulates the functional activity of monocytes

Effects of human interleukin 3, macrophage and granulocyte-macrophage colony-stimulating factor on monocyte function following autologous bone marrow transplantation

The effects of human interleukin 3 (IL-3), macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were studied on the functional activity of human peripheral blood monocytes from healthy individuals and from eight patients at 4, 8 and 12 weeks following autologous bone marrow transplantation (ABMT). Functions studied included superoxide production, phagocytosis of Candida albicans and reduction of 3-[4,5-dimethylthiazol-2-yl]-2.5-diphenyl tetrazolium bromide (MTT). IL-3 and GM-CSF significantly enhanced the oxidative metabolism of monocytes from healthy individuals, while the effect of M-CSF was moderate. A considerable variability between healthy individuals was found in both resting and cytokine-stimulated monocytes with regard to superoxide production. All three investigated CSFs. i.e. IL-3, M-CSF and GM-CSF did not affect phagocytosis of C. albicans by the cells or their metabolic activity (reduction of MTT). In ABMT patients no deficit in the functional activity of monocytes was found at any time after transplantation and all three CSFs investigated did not modulate the functional activity of the cells. These results suggest that monocytes do not have a major role in infectious complications post-ABMT.

Correlation between cutaneous sarcoidosis and systemic sarcoidosis.

Twenty patients with cutaneous sarcoidosis and 21 patients carrying isolated skin sarcoids were studied. (We use the term 'sarcoid' to emphasize that exclusively skin was altered.) Both groups were compared by clinical and histological patterns and certain data concerning the state of the mononuclear phagocyte system (MPS). It was found that skin lesions in sarcoids and sarcoidosis do not differ regarding either in clinical or histological manifestations. The changes in the functional activity of monocytes and macrophages were the same. The data obtained allow us to suggest that sarcoids should be regarded as a systemic disease connected with changes in the MPS reaction.

Correlation between cutaneous sarcoidosis and systemic sarcoidosis.

Twenty patients with cutaneous sarcoidosis and 21 patients carrying isolated skin sarcoids were studied. (We use the term 'sarcoid' to emphasize that exclusively skin was altered.) Both groups were compared by clinical and histological patterns and certain data concerning the state of the mononuclear phagocyte system (MPS). It was found that skin lesions in sarcoids and sarcoidosis do not differ regarding either in clinical or histological manifestations. The changes in the functional activity of monocytes and macrophages were the same. The data obtained allow us to suggest that sarcoids should be regarded as a systemic disease connected with changes in the MPS reaction.

Regulation of M-CSF Expression by M-CSF: Role of Protein Kinase C and Transcription Factor NFkB

Macrophage-colony-stimulating factor (M-CSF), also referred to as CSF-1, regulates the survival, growth, differentiation and functional activity of monocytes by binding to a single class of high-affinity cell surface receptors, known to be the product of the c-fms protooncogene. The detection of both M-CSF and c-fms expression by cells of the monocyte lineage has suggested that M-CSF may act by an autocrine mechanism. Interestingly, it has been shown that M-CSF can induce the expression of its own gene. Although sensitivity to M-CSF can be modulated by regulation of receptor expression and function, M-CSF responsiveness is largely determined at a postreceptor level. To date, little is known about the intracellular pathway of M-CSF signal transduction. We have therefore investigated the changes in protein kinase C (PKC) activity upon exposure of monocytes to M-CSF. We show that M-CSF activates and translocates PKC. Inhibition of PKC by the isoquinoline derivative H7 abolishes induction of M-CSF by M-CSF. Furthermore, activation of PKC was pertussis-toxin-sensitive and was associated with the detection of an NF kappa B protein in nuclear extracts of M-CSF-induced blood monocytes but not in monocytes exposed to medium treatment only. The results suggest that M-CSF induction of M-CSF involves G proteins, PKC and NF kappa B.

Expression of c-jun Protooncogene in Human Myelomonocytic Cells

A prototypic "immediate early" gene, c-fos, has been extensively investigated in relation to the differentiation and activation of myelomonocytic cells. The c-fos gene product is associated in transcriptional complexes with the c-jun product. These protooncogenes are part of the regulatory network of gene expression. The present study was designed to investigate expression of the c-jun protooncogene in human circulating myelomonocytic cells. We found that c-jun is constitutively expressed in normal monocytes and granulocytes, whereas low levels of transcripts are found in lymphocytes. Acute myelogenous leukemia (AML) samples of French-American-British Cooperative Group (FAB) subtypes 1 through 4 express appreciable levels of this protooncogene. Normal phytohemagglutinin (PHA)-activated lymphocytes express high levels of c-jun. Expression in normal myelomonocytic cells is detectable even after 18 hours of culture. The c-jun transcripts in myelomonocytic cells have a half-life of approximately 20 minutes and are superinduced by cycloheximide, which affects both the degradation rate of mRNA and the transcriptional activity of the c-jun gene. Functional activation of monocytes and granulocytes with phorbol esters, lipopolysaccharide, and tumor necrosis factor (TNF) increase c-jun expression. This induction is rapid, transient, and does not require intervening protein synthesis. Runoff experiments showed that in freshly isolated untreated monocytes, the c-jun gene is constitutively transcribed, and that induction by lipopolysaccharide is at least in part at the transcriptional level. Moreover, lipopolysaccharide (LPS) treatment reduced the degradation rate of c-jun transcripts, prolonging the half-life to approximately two hours. Expression of c-jun in resting and activated monocytes and granulocytes suggests that this protooncogene may play a role in the differentiation and activation of cells belonging to the myelomonocytic lineage.