Proinflammatory Monocyte Activation Research Articles

Pro-inflammatory activation of monocytes in patients with immunoinflammatory rheumatic diseases

Pro-inflammatory activation of monocytes in patients with immunoinflammatory rheumatic diseases

Proinflammatory Activation of Monocytes in Patients with Immunoinflammatory Rheumatic Diseases.

. The objective of this study was to evaluate the proinflammatory activation of circulating monocytes in patients with IRDs. . The study involved 149 participants (53 patients with rheumatoid arthritis (RA), 45patients with systemic lupus erythematosus (SLE), 34 patients with systemic scleroderma (SSc), and 17participants without IRDs) 30 to 65 years old. Basal and lipopolysaccharide (LPS)-stimulated secretion of monocytes was studied in a primary culture of monocytes obtained from blood by immunomagnetic separation. Quantitative assessment of the cytokines tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), as well as the chemokine monocyte chemoattractant protein-1 (MCP-1) was carried out in the culture fluid by ELISA. Proinflammatory activation of monocytes was calculated as the ratio of LPS-stimulated and basal secretions. . It was shown that the basal secretion of all studied cytokines was significantly increased in all groups of patients with IRDs, except for the secretion of IL-1β in the SLE group, compared to the control. LPS-stimulated secretion of TNF-α was increased and MCP-1 was decreased in patients with IRDs compared to the control group; LPS-stimulated IL-1β secretion only in the SSc group significantly differed from the control group. In the RA group, monocyte activation was reduced for all cytokines compared to the control; in the SLE group, for TNF-α and MCP-1; in the SSc group, for MCP-1. . The decrease in proinflammatory activation of monocytes in patients with IRDs is due to a high level of basal secretion of cytokines, which can lead to disruption of the adequate immune response in these diseases and is an important link in the pathogenesis of chronic inflammation.

Pro-inflammatory activation of monocytes in patients with immunoinflammatory rheumatic diseases

The pathogenesis of immunoinflammatory rheumatic diseases (IRDs) is based on chronic inflammation, one of the key mechanisms of which may be abnormal activation of macrophages, leading to further disruption of the immune system.The aim – to evaluate the pro-inflammatory activation of circulating monocytes in patients with IRDs.Material and methods. The study included 149 participants: 53 patients with rheumatoid arthritis (RA), 45 – with systemic lupus erythematosus (SLE), 34 – with systemic scleroderma (SSc) and 17 participants without IRD, aged 30 to 65 years. Basal and lipolysaccharide (LPS)-stimulated secretion of monocytes was studied in a primary culture of monocytes obtained by immunomagnetic separation from blood. Quantitative assessment of the cytokines tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and the monocyte chemoattractant protein-1 (MCP-1) was carried out in the culture fluid by ELISA. Pro-inflammatory activation of monocytes was calculated as the ratio of LPS-stimulated and basal secretions.Results. It was shown that the basal secretion of all studied cytokines was significantly increased in all groups of patients with IRDs, except for the secretion of IL-1β in the SLE group, compared with the control. LPS-stimulated secretion of TNF-α was increased and MCP-1 was decreased in patients with IRDs compared to the control group; LPS-stimulated IL-1β secretion only in the SSc group was significantly different from the control group. In the RA group, monocyte activation was reduced for all cytokines compared to the control, in the SLE group – for TNF-α and MCP-1, in the SSc group – for MCP-1.Conclusion. The decrease in pro-inflammatory activation of monocytes in patients with IRDs is due to a high level of basal secretion of cytokines, which can lead to disruption of the adequate immune response in these diseases and is an important link in the pathogenesis of chronic inflammation.

Cellular RNA and DNA sensing pathways are essential for the dose-dependent response of human monocytes to ionizing radiation.

Circulating monocytes are important players of the inflammatory response to ionizing radiation (IR). These IR-resistant immune cells migrate to radiation-damaged tissues and differentiate into macrophages that phagocytize dying cells, but also facilitate inflammation. Besides the effect of damage-associated molecular patterns, released from irradiated tissues, the inflammatory activation of monocytes and macrophages is largely dependent on IR-induced DNA damage and aberrant transcriptional activity, which may facilitate expression of type I interferons (IFN-I) and numerous inflammation-related genes. We analyzed the accumulation of dsRNA, dsDNA fragments, and RNA:DNA hybrids in the context of induction of RNA-triggered MAVS-mediated and DNA-triggered STING-mediated signaling pathways, in primary human monocytes and a monocytic cell line, THP1, in response to various doses of gamma IR. We found that exposure to lower doses (<7.5 Gy) led to the accumulation of dsRNA, along with dsDNA and RNA:DNA hybrids and activated both MAVS and STING pathway-induced gene expression and signaling activity of IFN-I. Higher doses of IR resulted in the reduced dsRNA level, degradation of RNA-sensing mediators involved in MAVS signaling and coincided with an increased accumulation of dsDNA and RNA:DNA hybrids that correlated with elevated STING signaling and NF-κB-dependent gene expression. While both pathways activate IFN-I expression, using MAVS- and STING-knockout THP1 cells, we identified differences in the spectra of interferon-stimulated genes (ISGs) that are associated with each specific signaling pathway and outlined a large group of STING signaling-associated genes. Using the RNAi technique, we found that increasing the dose of IR activates STING signaling through the DNA sensor cGAS, along with suppression of the DDX41 helicase, which is known to reduce the accumulation of RNA:DNA hybrids and thereby limit cGAS/STING signaling activity. Together, these results indicate that depending on the applied dose, IR leads to the activation of either dsRNA-induced MAVS signaling, which predominantly leads to the expression of both pro- and anti-inflammatory markers, or dsDNA-induced STING signaling that contributes to pro-inflammatory activation of the cells. While RNA:DNA hybrids boost both MAVS- and STING-mediated signaling pathways, these structures being accumulated upon high IR doses promote type I interferon expression and appear to be potent enhancers of radiation dose-dependent pro-inflammatory activation of monocytes.

LPS differentially affects expression of CD14 and CCR2 in monocyte subsets of Post-STEMI patients with hyperglycemia

AimsFollowing ST-segment elevation myocardial infarction (STEMI), recruitment and activation of monocytes [classical (CD14++CD16-CCR2++), intermediate (CD14++CD16+CCR2+), non-classical (CD14LowCD16++CCR2Low)] are needed for myocardial wound healing. Monocyte surface receptor CC chemokine receptor type 2 (CCR2) is responsible for monocyte chemotaxis to sites of inflammation and the lipopolysaccharide (LPS)-binding protein co-receptor, CD14, is involved in pro-inflammatory monocyte activation. The purpose of this investigation was to determine the effects of ex-vivo LPS activation on monocyte subset CD14 and CCR2 expression in post-STEMI individuals with normal and elevated random blood glucose. MethodsPost-STEMI subjects were identified as normal random glucose (NG, <98 mg/dL, n = 13) or impaired random glucose (IG, ≥98 mg/dL, n = 26) and monocytes were analyzed for non-activated and LPS-activated (1 µg/mL for 4 h) CCR2 and CD14 expression. ResultsNon-activated intermediate monocytes from IG showed decreased CD14 expression when compared to NG, which was maintained following LPS-activation. The NG group showed a larger absolute reduction in classical CCR2 expression, leading to a significant difference between NG and IG following LPS-activation. ConclusionResults suggest a heightened response to pro-inflammatory activation in IG following STEMI, which may impair or delay post-STEMI myocardial healing, and thus increase the incidence of chronic heart failure. NIH 1R34HL121402.

Monocyte activation in atherosclerosis associated with autoimmune rheumatic diseases

Background and Aims : The pro-inflammatory activation of monocytes may responsible for the the tendency to chronic inflammation, which underlies autoimmune rheumatic diseases (ARDs) and atherosclerosis. It is known that atherosclerosis progression is accelerated in patients with ARDs. The aim of this study is to investigate the association of monocyte activation and carotid atherosclerosis in ARDs patients.

Monocyte activation in patients with carotid atherosclerosis and obesity

Background and Aims : Currently, obesity is considered as a pro-inflammatory condition, which contributes to increased atherogenesis and the development of cardiovascular diseases. This pilot study was aimed to evaluate the role of pro-inflammatory monocyte activation in atherosclerosis development in obese patients.

MiR-155-overexpressing monocytes resemble HLAhighISG15+ synovial tissue macrophages from patients with rheumatoid arthritis and induce polyfunctional CD4+ T-cell activation.

MicroRNAs (miRs) are known to regulate pro-inflammatory effector functions of myeloid cells, and miR dysregulation is implicated in rheumatoid arthritis (RA), a condition characterized by inflammation and destruction of the joints. We showed previously that miR-155 is increased in myeloid cells in RA and induces pro-inflammatory activation of monocytes and macrophages; however, its role at the interface between innate and adaptive immunity was not defined. Here, RNA-sequencing revealed that overexpression of miR-155 in healthy donor monocytes conferred a specific gene profile which bears similarities to that of RA synovial fluid-derived CD14+ cells and HLAhighISG15+ synovial tissue macrophages, both of which are characterized by antigen-presenting pathways. In line with this, monocytes in which miR-155 was overexpressed, displayed increased expression of HLA-DR and both co-stimulatory and co-inhibitory molecules, and induced activation of polyfunctional T cells. Together, these data underpin the notion that miR-155-driven myeloid cell activation in the synovium contributes not only to inflammation but may also influence the adaptive immune response.

Transcriptome and physiological effects of toxaphene on the liver-gonad reproductive axis in male and female largemouth bass (Micropterus salmoides)

Toxaphene is an organochlorine pesticide and environmental contaminant that is concerning due to its atmospheric transport and persistence in soil. In Florida, toxaphene and other organochlorine pesticides were used heavily in agriculture on the north shore of Lake Apopka and they are still detectable in soil. Wild largemouth bass that inhabit the lake and the marshes along the north shore have been exposed to a variety of organochlorine pesticides including dieldrin, methoxychlor, and p,p′-DDE, among others. While these other organochlorine pesticides have been studied for their endocrine disrupting effects in largemouth bass, there is little information for toxaphene. In this study, male and female largemouth bass were given food containing 50 mg/kg toxaphene for almost 3 months, to achieve tissue levels similar to those found in fish at Lake Apopka. Sex-specific toxicity was then evaluated by measuring various reproductive endpoints and transcriptomic changes. In females, gonadosomatic index showed a trend towards reduction (p = 0.051) and plasma vitellogenin was reduced by ~40% relative to controls. However plasma levels of 17β-estradiol and testosterone were not perturbed by toxaphene exposure. These data suggest that toxaphene does not act as a weak estrogen as many other organochlorine pesticides do, but rather appears to be acting as an antiestrogen in female fish. There were no obvious changes in the gonadosomatic index and plasma hormones in male bass. However, ex vivo explant experiments revealed that toxaphene prevented human chorionic gonadotropin-stimulated testosterone production in the testis. This suggested that toxaphene had anti-androgenic effects in males. Subsequent transcriptomic analyses of the testis revealed that androgen receptor/beta-2-microglobulin signaling was up-regulated while insulin-related pathways were suppressed with toxaphene, which could be interpreted as a compensatory response to androgen suppression. In the male liver, the transcriptome analysis revealed an overwhelming suppression in immune-related signaling cascades (e.g. lectin-like receptor and ITSM-Containing Receptor signaling, CD16/CD14 Proinflammatory Monocyte Activation, and CD38/CD3-JUN/FOS/NF-kB Signaling in T-cell Proliferation). Overall, this study showed that toxaphene induced sex-specific effects. The transcriptomic and physiological responses observed can contribute to the development of adverse outcome pathways for toxaphene exposure in fish.

Patients with idiopathic endplate inflammation displayed aberrant Th17 responses resulting in proinflammatory monocyte activation

Endplate inflammation remains a difficult task to diagnose and treat, partly due to the absence of in-depth understanding of the cellular and molecular factors driving this condition. In the current study, we investigated the circulating immune cells in patients with idiopathic endplate inflammation. Compared to healthy controls, the patients with endplate inflammation presented a significant upregulation of Th17 cells, characterized by higher frequencies of circulating IL-17+CD4+ T cells examined directly ex vivo and after PMA and ionomycin (PMA/I) stimulation. The frequency of Th17 cells in patients was not correlated with patient age, sex, or smoking status, but was significantly correlated with patient BMI. The total CD4+ T cells from patients with end plate inflammation also presented significantly higher levels of IL-17 secretion directly ex vivo and after PMA/I stimulation. The IL-17 secretion was primarily mediated by CCR4+CCR6+ CD4+ T cells, followed by CCR4-CCR6+ CD4+ T cells and was nearly absent in CCR4-CCR6- CD4+ T cells. Monocytes incubated with CCR4+CCR6+ CD4+ T cells presented significantly higher MHC class II expression, as well as higher CD80 and CD86 expression. The secretion of IL-6 and TNF was significantly higher in cell cultures containing CCR4+CCR6+ CD4+ T cells than in cell cultures containing CCR4-CCR6- CD4+ T cells. These effects were reduced when the IL-17A cytokine was neutralized. Together, we identified a systemic upregulation of Th17 responses that could contribute to proinflammatory monocyte activation in patients with endplate inflammation.

Regulation of proinflammatory monocyte activation by the kynurenine-AhR axis underlies immunometabolic control of depressive behavior in mice.

Elevated kynurenine (Kyn) production from tryptophan (Trp) metabolism is a biomarker of immune dysregulation in depression, but its mechanistic contributions to the behavioral symptoms are poorly defined. In this study, Kyn was shown to be a metabolic regulator of proinflammatory monocytes that orchestrated peripheral immune activation and neuroinflammation in depressive mice. Kyn-induced depressive behavior was paralleled by brain infiltration of proinflammatory monocytes and astrocytic activation. Kyn enhanced chemokine (C-C motif) ligand-2-mediated chemotaxis of monocytes and their proinflammatory capability on cocultured astrocytes in vitro, which involved the activation of aryl hydrocarbon receptor (AhR) signaling. Kyn augmented, whereas pharmacological AhR blockade rescued, systemic inflammation-induced monocyte trafficking, neuroimmune disturbance, and depressive-like behavior in mice. The behavior-exacerbating effects of the Kyn-AhR axis were dampened with prior depletion of functional monocytes in the periphery. The findings in our study extend understanding of an immunologic effect of Kyn that links Trp metabolism and inflammatory signaling in depression pathology, with potential therapeutic implications for depressive disorders.-Zang, X., Zheng, X., Hou, Y., Hu, M., Wang, H., Bao, X., Zhou, F., Wang, G., Hao, H. Regulation of proinflammatory monocyte activation by the kynurenine-AhR axis underlies immunometabolic control of depressive behavior in mice.

3857Activation of the GIP system attenuates pathological vascular remodeling by decreasing infiltration and proinflammatory activation of monocytes in ApoE−/− mice

3857Activation of the GIP system attenuates pathological vascular remodeling by decreasing infiltration and proinflammatory activation of monocytes in ApoE−/− mice

The incretin hormone GIP decreases vascular infiltration and proinflammatory activation of monocytes in ApoE-/- mice

Activation of the GLP-1-System (Glucagon-like-peptide-1) has been shown to prevent the development of atherosclerosis in experimental models and to reduce cardiovascular mortality in patients with diabetes. Recent evidence also suggested anti-atherosclerotic effects of the other main incretin GIP (glucose-dependent insulinotropic peptide) in mice, however with yet elusive mechanism.

ERBB signaling attenuates proinflammatory activation of nonclassical monocytes.

Immune activation in chronic systolic heart failure (HF) correlates with disease severity and prognosis. Recombinant neuregulin-1 (rNRG-1) is being developed as a possible therapy for HF, based on the activation of ERBB receptors in cardiac cells. Work in animal models of HF led us to hypothesize that there may be direct effects of NRG-1 on immune system activation and inflammation. We investigated the expression of ERBB receptors and the effect of rNRG-1 isoform glial growth factor 2 (GGF2) in subpopulations of peripheral blood mononuclear cells (PB MNCs) in subjects with HF. We found that human monocytes express both ERBB2 and ERBB3 receptors, with high interindividual variability among subjects. Monocyte surface ERBB3 and TNF-α mRNA expression were inversely correlated in subjects with HF but not in human subjects without HF. GGF2 activation of ERBB signaling ex vivo inhibited LPS-induced TNF-α production, specifically in the CD14lowCD16+ population of monocytes in a phosphoinositide 3-kinase-dependent manner. GGF2 suppression of TNF-α correlated directly with the expression of ERBB3. In vivo, a single dose of intravenous GGF2 reduced TNF-α expression in PB MNCs of HF subjects participating in a phase I safety study of GGF2. These results support a role for ERBB3 signaling in the regulation of TNF-α production from CD14lowCD16+ monocytes and a need for further investigation into the clinical significance of NRG-1/ERBB signaling as a modulator of immune system function.NEW & NOTEWORTHY This study identified a novel role of neuregulin-1 (NRG-1)/ERBB signaling in the control of proinflammatory activation of monocytes. These results further improve our fundamental understanding of cardioprotective effects of NRG-1 in patients with heart failure.

SIGNIFICANCE OF M1 AND M2 POLARIZATION OF MONOCYTES-MACROPHAGES IN THE BLOOD FOR ATHEROSCLEROSIS RISK ASSESSMENT IN TYPE 2 DIABETES COMPARING WITH CORONARY HEART DISEASE

Aim. To assess the phenotypes of proinflammatory (M1) and anti-inflammatory (M2) activation of blood monocytes in type 2 diabetes (DM2) comparing to coronary heart disease patients (CHD). Material and methods. Totally, 55 CHD patients assessed, of those 28 (11M/17F) were first time diagnosed with DM2 at current hospitalization (HbA 1c level 9,7% SD=2,4), not taking previously any glucose lowering therapy; and 27 patients with CHD (20M, 7F), with no glucose metabolism disorders. By immune enzyme assay method (IEA) proinflammatory monocyte activation was evaluated by spontaneous and interferon gamma (IFN-ɣ) induced secretion of proinflammatory cytokine tumour necrosis factor alpha (TNF-α), and anti-inflammatory activation of monocytes by spontaneous and interleukin-4 (IL-4) induced secretion of anti-inflammatory cytokine CCL18. Results. There was found an increased ability of monocytes in DM2 patients to secrete proand anti-inflammatory cytokines comparing to the controls and CHD patients. Basal TNF-α secretion was higher than control level 2,8 times, and stimulated — 2,2 times. Values of the basal and stimulated TNF-α secretion in CHD patients were significantly lower than in controls. There was positive correlation of HbA 1c level and basal secretion of TNF-α. Basal and stimulated secretion of anti-inflammatory cytokine CCL18 in DM2 patients was significantly higher than control level — 28 pg/mL (SD=3) and 1158 (SD=68) pg/mL of the cultural medium, respectively, and in CHD patients these parameters were lower than the control level — 0,26 pg/mL (SD=0,14) and 65 (SD=33) pg/mL, respectively. Conclusion. In DM2 there is disbalance of M1/M2 activation of monocytes comparing to controls and CHD, that points on overactivation by proinflammatory phenotype.

Treatment with chondroitin sulfate to modulate inflammation and atherogenesis in obesity

Background and aimsOsteoarthritic patients treated with high doses of chondroitin sulfate (CS) have a lower incidence of coronary heart disease – but the mechanistic aspects of these beneficial effects of CS remain undefined. We examined how CS treatment affects the formation of atheroma via interaction with endothelial cells and monocytes. MethodsWe characterized arterial atheromatous plaques by multiphoton microscopy and serum pro-inflammatory cytokines by immunoenzymatic techniques in obese mice receiving CS (1 g/kg/day, i.p.) or vehicle for 6 days. Effects of CS on signaling pathways, cytokine secretion and macrophage migration were evaluated in cultures of human coronary endothelial cells and in a monocyte cell line stimulated with TNF-α by Western blot, immunoenzymatic techniques and transwell migration assays. ResultsTreatment of obese mice with CS reduced the extension of foam cell coverage in atheromatous plaques of arterial bifurcations by 62.5%, the serum concentration of IL1β by 70%, TNF-α by 82% and selected chemokines by 25–35%. Cultures of coronary endothelial cells and monocytes stimulated with TNF-α secreted less pro-inflammatory cytokines in the presence of CS (P < 0.01). CS reduced the activation of the TNF-α signaling pathway in endothelial cells (pErk 36% of reduction, and NFκB 33% of reduction), and the migration of activated monocytes to inflamed endothelial cells in transwells (81 ± 6 vs. 13 ± 2, P < 0.001). ConclusionsCS interferes with the pro-inflammatory activation of monocytes and endothelial cells driven by TNF-α thus reducing the propagation of inflammation and preventing the formation of atherosclerotic plaques.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Red Blood Cell Dysfunction Induced by High-Fat Diet: Potential Implications for Obesity-Related Atherosclerosis.

High-fat diet (HFD) promotes endothelial dysfunction and proinflammatory monocyte activation, which contribute to atherosclerosis in obesity. We investigated whether HFD also induces the dysfunction of red blood cells (RBCs), which serve as a reservoir for chemokines via binding to Duffy antigen receptor for chemokines (DARC). A 60% HFD for 12 weeks, which produced only minor changes in lipid profile in C57/BL6 mice, markedly augmented the levels of monocyte chemoattractant protein-1 bound to RBCs, which in turn stimulated macrophage migration through an endothelial monolayer. Levels of RBC-bound KC were also increased by HFD. These effects of HFD were abolished in DARC(-/-) mice. In RBCs from HFD-fed wild-type and DARC(-/-) mice, levels of membrane cholesterol and phosphatidylserine externalization were increased, fostering RBC-macrophage inflammatory interactions and promoting macrophage phagocytosis in vitro. When labeled ex vivo and injected into wild-type mice, RBCs from HFD-fed mice exhibited ≈3-fold increase in splenic uptake. Finally, RBCs from HFD-fed mice induced increased macrophage adhesion to the endothelium when they were incubated with isolated aortic segments, indicating endothelial activation. RBC dysfunction, analogous to endothelial dysfunction, occurs early during diet-induced obesity and may serve as a mediator of atherosclerosis. These findings may have implications for the pathogenesis of atherosclerosis in obesity, a worldwide epidemic.

Kruppel-Like Factor 2-Mediated Suppression of MicroRNA-155 Reduces the Proinflammatory Activation of Macrophages.

ObjectiveRecent evidence indicates that significant interactions exist between Kruppel-like factor 2 (KLF2) and microRNAs (miRNAs) in endothelial cells. Because KLF2 is known to exert anti-inflammatory effects and inhibit the pro-inflammatory activation of monocytes, we sought to identify how inflammation-associated miR-155 is regulated by KLF2 in macrophages.Approach and ResultsPeritoneal macrophages from wild-type (WT) C57Bl/6 mice were transfected with either recombinant adenovirus vector expressing KLF2 (Ad-KLF2) or siRNA targeting KLF2 (KLF2-siRNA) for 24 h–48 h, then stimulated with oxidized low-density lipoproteins (ox-LDL, 50 μg/mL) for 24 h. Quantitative real-time polymerase chain reaction showed that KLF2 markedly reduced the expression of miR-155 in quiescent/ox-LDL-stimulated macrophages. We also found that the increased expression of miR-155, monocyte chemoattractant protein (MCP-1) and interleukin (IL)-6 and the decreased expression of the suppressor of cytokine signaling (SOCS)-1 and IL-10 in ox-LDL-treated macrophages were significantly suppressed by KLF2. Most importantly, over-expression of miR-155 could partly reverse the suppressive effects of KLF2 on the inflammatory response of macrophages. Conversely, the suppression of miR-155 in KLF2 knockdown macrophages significantly overcame the pro-inflammatory properties associated with KLF2 knockdown. Finally, Ad-KLF2 significantly attenuated the diet-induced formation of atherosclerotic lesions in apolipoprotein E-deficient (apoE-/-) mice, which was associated with a significantly reduced expression of miR-155 and its relative inflammatory cytokine genes in the aortic arch and in macrophages.ConclusionKLF2-mediated suppression of miR-155 reduced the inflammatory response of macrophages.

Modulation of pro-inflammatory activation of monocytes and dendritic cells by aza-bis-phosphonate dendrimer as an experimental therapeutic agent.

IntroductionOur objective was to assess the capacity of dendrimer aza-bis-phosphonate (ABP) to modulate phenotype of monocytes (Mo) and monocytes derived dendritic cells (MoDC) activated in response to toll-like receptor 4 (TLR4) and interferon γ (IFN- γ) stimulation.MethodsMo (n = 12) and MoDC (n = 11) from peripheral blood of healthy donors were prepared. Cells were preincubated or not for 1 hour with dendrimer ABP, then incubated with lipopolysaccharide (LPS; as a TLR4 ligand) and (IFN-γ) for 38 hours. Secretion of tumor necrosis factor α (TNFα), interleukin (IL) -1, IL-6, IL-12, IL-10 and IL-23 in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Bead Array. Differentiation and subsequent maturation of MoDC from nine donors in the presence of LPS were analyzed by flow cytometry using CD80, CD86, CD83 and CD1a surface expression as markers.ResultsMo and MoDC were orientated to a pro-inflammatory state. In activated Mo, TNFα, IL-1β and IL-23 levels were significantly lower after prior incubation with dendrimer ABP. In activated MoDC, dendrimer ABP promoted IL-10 secretion while decreasing dramatically the level of IL-12. TNFα and IL-6 secretion were significantly lower in the presence of dendrimer ABP. LPS driven maturation of MoDC was impaired by dendrimer ABP treatment, as attested by the significantly lower expression of CD80 and CD86.ConclusionOur data indicate that dendrimer ABP possesses immunomodulatory properties on human Mo and MoDC, in TLR4 + IFN-γ stimulation model, by inducing M2 alternative activation of Mo and promoting tolerogenic MoDC.