Reduced Interleukin-2 Production Research Articles

Efficacy of Tounongsan decoction on pyogenic liver abscess: network pharmacology and clinical trial validation.

To elucidate the molecular mechanisms governing the effect of Tounongsan decoction (, TNS) on the pyogenic liver abscess. Based on oral bioavailability and drug-likeness, the main active components of TNS were screened using the Traditional Chinese Medicine Systems Pharmacology platform. The GeneCard and UniProt databases were used to establish a database of pyogenic liver abscess targets. The interactive network map of drug-ingredients-target-disease was constructed using Cytoscape software (Version 3.7.2). A protein-protein interaction network was constructed using the STRING database, and the related protein interaction relationships were analyzed. biological process of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for the core targets. Finally, a clinical trial was performed to verify the reliability of the network pharmacology. Forty active components of TNS decoction were obtained, and 61 potential targets and 11 proteins were identified. Pathways involved in the treatment of pyogenic liver abscess include the phosphatidylinositide 3-kinases-protein kinase B (PI3K-AKT), advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE), and tumor necrosis factor (TNF) signaling pathways. The results of network pharmacology analysis combined with clinical trials validated that TNS decoction could alleviate the inflammatory response of pyogenic liver abscesses by decreasing interleukin 6 (IL-6) levels. TNS decoction has the characteristics of being multi-system, multi-component, and multi-target. Active ingredients in TNS, such as quercetin, kaempferol, fisetin, and β-sitosterol, have strong potential to be candidate drugs for treating pyogenic liver abscesses. The possible mechanism of TSN decoction includes regulating immune and inflammatory responses and reducing IL-6 production to control inflammatory development.

Treponema pallidum recombinant protein Tp47 enhanced interleukin-6 secretion in human dermal fibroblasts through the toll-like receptor 2 via the p38, PI3K/Akt, and NF-κB signalling pathways.

Interleukin-6 (IL-6) is a multi-effective cytokine involved in multiple immune responses. Whether fibroblasts also turn out to be a cytokine IL-6 factory during interaction with Treponema pallidum is not yet understood. To explore whether fibroblasts participate in inflammation due to syphilis, a series of experiments were performed to explore the role of T. pallidum lipoprotein Tp47 in IL-6 production in human dermal fibroblasts. The Toll-like receptor 2 (TLR2) and participating signalling pathways in this process were also evaluated. The results showed that the expressions of IL-6 and the protein levels of TLR2 in fibroblasts were upregulated after stimulation with Tp47, and this effect was impeded by the TLR2 inhibitor C29. In addition, Tp47 promoted the phosphorylation of p38, PI3K/Akt, and nuclear factor-kappaB (NF-κB), and the translocation of NF-κB in fibroblasts. Moreover, p38, PI3K, and NF-κB inhibitors significantly reduced IL-6 production in fibroblasts stimulated with Tp47. Furthermore, the TLR2 inhibitor C29 inhibited the phosphorylation of p38, Akt, and NF-κB, and the translocation of NF-κB in fibroblasts. In conclusion, our results showed that Tp47 enhanced IL-6 secretion in human dermal fibroblasts through TLR2 via p38, PI3K/Akt, and NF-κB signalling pathways. These findings contribute to our understanding of syphilis inflammation.

Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids.

In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2-31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32-61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered.

Digested Human Colostrum Reduces Interleukin-8 Production in Induced Human Intestinal Epithelial Cells.

Little is known about the impact of human colostrum on infant intestinal health following digestion. The aim of this study was to compare the effect of digested versus undigested human colostrum on inflammation and cytotoxicity in human intestinal epithelial cells (Caco2BBe) stimulated with lipopolysaccharides (LPS) or tumor necrosis factor (TNF). Colostrum samples (days 2–8 postpartum) from ten mothers of preterm infant were applied. Caco2BBe cells were pretreated by digested or undigested colostrum before stimulation with LPS or TNF. The inflammatory response was determined by measuring the production of interleukin-8 (IL-8) from cells using enzyme linked immunosorbent assay (ELISA). Cytotoxicity was examined by measuring the release of lactate dehydrogenase (LDH) from the cells. Digested colostrum significantly reduced IL-8 production under LPS and TNF stimulation compared with undigested colostrum. Individual colostrum samples exhibited wide variance in the ability to suppress IL-8 production and cytotoxicity in Caco2BBe cells. In vitro-digested human colostrum suppressed an inflammatory response more than undigested human colostrum in an induced intestinal cell culture model.

Transcriptional regulation and small compound targeting of ACE2 in lung epithelial cells.

Angiotensin-converting enzyme 2 (ACE2) is the receptor of COVID-19 pathogen SARS-CoV-2, but the transcription factors (TFs) that regulate the expression of the gene encoding ACE2 (ACE2) have not been systematically dissected. In this study we evaluated TFs that control ACE2 expression, and screened for small molecule compounds that could modulate ACE2 expression to block SARS-CoV-2 from entry into lung epithelial cells. By searching the online datasets we found that 24 TFs might be ACE2 regulators with signal transducer and activator of transcription 3 (Stat3) as the most significant one. In human normal lung tissues, the expression of ACE2 was positively correlated with phosphorylated Stat3 (p-Stat3). We demonstrated that Stat3 bound ACE2 promoter, and controlled its expression in 16HBE cells stimulated with interleukin 6 (IL-6). To screen for medicinal compounds that could modulate ACE2 expression, we conducted luciferase assay using HLF cells transfected with ACE2 promoter-luciferase constructs. Among the 64 compounds tested, 6-O-angeloylplenolin (6-OAP), a sesquiterpene lactone in Chinese medicinal herb Centipeda minima (CM), represented the most potent ACE2 repressor. 6-OAP (2.5 µM) inhibited the interaction between Stat3 protein and ACE2 promoter, thus suppressed ACE2 transcription. 6-OAP (1.25–5 µM) and its parental medicinal herb CM (0.125%–0.5%) dose-dependently downregulated ACE2 in 16HBE and Beas-2B cells; similar results were observed in the lung tissues of mice following administration of 6-OAP or CM for one month. In addition, 6-OAP/CM dose-dependently reduced IL-6 production and downregulated chemokines including CXCL13 and CX3CL1 in 16HBE cells. Moreover, we found that 6-OAP/CM inhibited the entry of SARS-CoV-2 S protein pseudovirus into target cells. These results suggest that 6-OAP/CM are ACE2 inhibitors that may potentially protect lung epithelial cells from SARS-CoV-2 infection.

The calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling.

S100B is frequently elevated in malignant melanoma. A regulatory mechanism was uncovered here in which elevated S100B lowers mRNA and secreted protein levels of interleukin-6 (IL6) and inhibits an autocrine loop whereby IL6 activates STAT3 signaling. Our results showed that S100B affects IL6 expression transcriptionally. S100B was shown to form a calcium-dependent protein complex with the p90 ribosomal S6 kinase (RSK), which in turn sequesters RSK into the cytoplasm. Consistently, S100B inhibition was found to restore phosphorylation of a nuclear located RSK substrate, CREB, which is a potent transcription factor for IL6 expression. Thus, elevated S100B reduces IL6-STAT3 signaling via RSK signaling pathway in malignant melanoma. Indeed, the elevated S100B levels in malignant melanoma cell lines correspond to low levels of IL6 and p-STAT3.

Zinc deficiency leads to reduced interleukin-2 production by active gene silencing due to enhanced CREMα expression in T cells

The micronutrient zinc is essential for proper immune function. Consequently, zinc deficiency leads to impaired immune function, as seen in decreased secretion of interleukin (IL)-2 by T cells. Although this association has been known since the late 1980s, the underlying molecular mechanisms are still unknown. Zinc deficiency and reduced IL-2 levels are especially found in the elderly, which in turn are prone to chronic diseases. Here, we describe a new molecular link between zinc deficiency and reduced IL-2 expression in T cells. The effects of zinc deficiency were first investigated invitro in the human T cell lines Jurkat and Hut-78 and complemented by invivo data from zinc-supplemented pigs. A short- and long-term model for zinc deficiency was established. Zinc levels were detected by flow cytometry and expression profiles were investigated on the mRNA and protein level. The expression of the transcription factor cAMP-responsive-element modulator α (CREMα) is increased during zinc deficiency invitro, due to increased protein phosphatase 2A (PP2A) activity, resulting in decreased IL-2 production. Additionally, zinc supplementation invivo reduced CREMα levels causing increased IL-2 expression. On epigenetic levels increased CREMα binding to the IL-2 promoter is mediated by histone deacetylase 1 (HDAC1). The HDAC1 activity is inhibited by zinc. Moreover, deacetylation of the activating histone mark H3K9 was increased under zinc deficiency, resulting in reduced IL-2 expression. With the transcription factor CREMα a molecular link was uncovered, connecting zinc deficiency with reduced IL-2 production due to enhanced PP2A and HDAC1 activity.

Cystatin C Plays a Sex-Dependent Detrimental Role in Experimental Autoimmune Encephalomyelitis

SUMMARYThe cysteine protease inhibitor Cystatin C (CST3) is highly expressed in the brains of multiple sclerosis (MS) patients and C57BL/6J mice with experimental autoimmune encephalomyelitis (EAE; a model of MS), but its roles in the diseases are unknown. Here, we show that CST3 plays a detrimental function in myelin oligodendrocyte glycoprotein 35–55 (MOG35–55)-induced EAE but only in female animals. Female Cst3 null mice display significantly lower clinical signs of disease compared to wild-type (WT) littermates. This difference is associated with reduced interleukin-6 production and lower expression of key proteins (CD80, CD86, major histocompatibility complex [MHC] II, LC3A/B) involved in antigen processing, presentation, and co-stimulation in antigen-presenting cells (APCs). In contrast, male WT and Cst3−/− mice and cells show no differences in EAE signs or APC function. Further, the sex-dependent effect of CST3 in EAE is sensitive to gonadal hormones. Altogether, we have shown that CST3 has a sex-dependent role in MOG35–55-induced EAE.

Identification of immunomodulatory peptides from zein hydrolysates

Food protein-derived bioactive peptides have been recognized as a promising candidate for the development of functional foods or nutraceuticals. Peptides exhibiting antioxidant, anti-proliferative and anti-hypertensive activities have been characterized from corn proteins while the knowledge on the presence of immunomodulatory peptides in corn proteins is limited. The objective of this study was to identify the immunomodulatory peptides from corn proteins using interleukin 6 (IL-6) in human macrophage-like U937 cells as the marker. Results indicated that zein protein hydrolysate digested by thermolysin showed a high yield of peptides with potent activity, which was then used for further fractionation by RP-HPLC. We identified five peptides using LC–MS/MS, among which, peptide FLPFNQL showed the highest activity reducing IL-6 production by 57.7% ± 6.1%.

Kappa-carrageenan sinus rinses reduce inflammation and intracellular Staphylococcus aureus infection in airway epithelial cells.

Chronic rhinosinusitis (CRS) is a common disease, often refractory to conventional antimicrobial treatment. In this study we investigate the antimicrobial and anti-inflammatory effects of adding kappa-carrageenan to a commercially available sinus rinse. Kappa-carrageenan was added to Flo CRS and Flo Sinus Care sinus rinses and applied directly to air-liquid interface cultured primary human nasal epithelial cells (HNECs) from 10 CRS patients. Inflammatory markers were measured using enzyme-linked immunosorbent assay. Kappa-carrageenan-supplemented sinus rinses were applied to human bronchial epithelial cells (HBEs) in the presence of different Staphylococcus aureus strains to observe the effect on intracellular infection rates. Flo Sinus Care with kappa-carrageenan rinse solutions resulted in a marked reduction of interleukin-6 (IL-6) production by HNECs from CRS patients (p = 0.007). Both Flo CRS and Flo Sinus Care rinses significantly reduced the S aureus intracellular infection of HBEs (p < 0.0001). The addition of kappa-carrageenan to both Flo CRS and Flo Sinus Care rinses further reduced the intracellular infection rate by an average of 2%. The commonly used sinus irrigation product Flo Sinus Care with added kappa-carrageenan reduces IL-6 production by HNECs in vitro. Flo CRS and Flo Sinus Care rinses significantly reduced S aureus intracellular infection rates of HBE cells. Our findings may have clinical relevance for CRS patient management.

Establishment of an Anti-acne Vulgaris Evaluation Method Based on TLR2 and TLR4-mediated Interleukin-8 Production.

To date, no cell-based assay that focuses on the prime cause of acne initiation through activation of toll-like receptor2 and 4 and interleukin-8 (IL-8) production exists. Herein, we present an assay that evaluates acne by determining TLR2 and 4 expression and activation. Viability of keratinocytes was determined by the MTT assay. IL-8 was evaluated by ELISA. Immunocytochemistry was performed for determining receptor expression. Lipoteichoic acid (LTA), peptidoglycan (PGN) and lipopolysaccharide (LPS) induced IL-8 production. Pre-treatment of cells with TLR2 and TLR4 inhibitors, before stimulation, reduced IL-8 production. Zinc gluconate was used for verification. Zinc can significantly suppress IL-8 production in the system. Treatment of cells with LTA+PGN or LPS resulted in increased TLR2 and TLR4 expression on the cell surface. This effect was prevented by zinc treatment. The measurement of IL-8 and TLR2 and TLR4 levels can be used for the evaluation of anti-acne treatment.

A novel whey tetrapeptide IPAV reduces interleukin-8 production induced by TNF-α in human intestinal Caco-2 cells

In the present study, an anti-inflammatory effect of enzymatic whey protein hydrolysate was examined in human intestinal Caco-2 cells. Stimulation of Caco-2 cells with tumour necrosis factor (TNF)-α induced interleukin (IL)-8 expression through the activation of nuclear factor kappa B p65, spleen tyrosine kinase and mitogen-activated protein kinases pathways. Pre-treatment of cells with whey protein hydrolysate reduced TNF-α-induced IL-8 expression. Mass spectrometry analysis has identified the active tetrapeptide IPAV, which corresponded to amino acids 94–97 of β-lactoglobulin. Pre-treatment of cells with IPAV reduced TNF-α-induced IL-8 expression and the increase in phosphorylation levels of key cellular signalling proteins. Pharmacological inhibition of peptide transporter 1 (PepT1), but not of calcium-sensing receptor, attenuated IPAV-mediated suppression of IL-8 expression. In summary, a novel anti-inflammatory tetrapeptide IPAV, derived from whey protein hydrolysate, reduced IL-8 expression induced by TNF-α. Our results suggest that IPAV, transported by PepT1, can suppress inflammatory signalling in intestinal cells.

In vitro effects of Zinc in soluble and homeopathic formulations on macrophages and astrocytes

Zinc is an important metal in body homeostasis. Zinc in soluble form (Zn2+) and homeopathic Zincum metallicum were tested in macrophages and astrocytes in order to investigate its potential toxic or therapeutic effects. We evaluated cell viability (WST assay), cytokine production such as tumour necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) by enzyme-linked immunosorbent assay (ELISA) and nitric oxide release by Griess reaction. The effect of zinc-depletion and high zinc pre-treatments on the cell adaptation capability was also investigated. In THP-1 macrophage cell line and in human primary macrophages, Zn2+ at sub-toxic doses (30μM) caused stimulation of TNF-α and IL-10 with different dynamics reaching the maximum peak at the zinc concentration 100μM, before the cell death. Highest doses (300μM) impaired dramatically cell vitality. Similar effects on cell viability were obtained also in C6 astrocytes, where Zn2+ slightly increased the nitric oxide release only in cells activated by one of the pro-inflammatory stimuli used in our cellular model (interferon gamma plus TNF-α). Zinc depletion markedly reduced IL-10 production and cell viability. Zincum metallicum did not cause toxicity in any cell type and showed some small stimulation in WST assay that was statistically significant in a few experimental conditions.

Anti-inflammatory effect of Varthemia iphionoides extracts against prostate cancer in vitro

Varthemia iphionoides is a Jordanian medicinal plant with several health-promoting properties, including antibacterial, antioxidant and anticancer activities. However, its anti-inflammatory properties have been poorly investigated up to date. The current study aimed to investigate the anti-inflammatory effect of V. iphionoides by measuring the production of interleukin-6 in response to a pro-inflammatory stimulus (bacterial lipopolysaccharide) in in vitro cell models of human MRC-5 and PC3 cells. We observed a significant reduction in lipopolysaccharide-induced interleukin-6 release in response to V. iphionoides (125 µg/mL) in both non-cancerous fibroblast MRC-5 and prostate cancerous PC3 cells. However, the anti-inflammatory effect of this medicinal plant was stronger when MRC-5 cells were treated with an aqueous extract, while the methanolic extract was more potent in PC3 cells. The effect of V. iphionoides in reducing interleukin-6 production was not due to its cytotoxicity, and future studies are required to elucidate the mechanisms of action by which this medicinal plant modulates inflammatory responses. In conclusion, the results of our study represent the first report of the potential protective effect of water and methanolic extracts of V. iphionoides against pro-inflammatory stimuli in fibroblasts and cancer cells of human origin, and it is critically important to identify the phytochemical compounds responsible for this effect.

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

The activation of the platelet-activating factor receptor (PAFR) is associated to a suppressor phenotype in macrophages and dendritic cells (DCs). In the present study, we investigated mechanisms underlying the production of the interleukin 10 (IL-10) through PAFR activation in murine DCs. For this purpose, BALB/c mice bone marrow-derived DCs were differentiated by GM-CSF treatment and stimulated with LPS in the presence of the PAFR antagonist WEB2086. Signalling pathways downstream to TLR4 activation were investigated. We found that LPS stimulus induced PAFR ligands generation by DCs, but it did not affect the PAFR expression. The LPS-induced IL-10 production was found to be partially dependent of PAFR, since it was reduced in the presence of WEB2086. The IL-10 production through PAFR activation was independent on CREB and PPARγ, as the treatment with selective inhibitors of these pathways did not affect the IL-10 production. TLR4 adaptor molecules (MyD88 and TRIF) expression, MAPK, or NF-κB (p105/50 and p65 subunits) activation pathways were also excluded, since they were not affected by the treatment with WEB2086. The blockage of PAFR by WEB2086 downregulated the STAT3 (Tyr705) phosphorylation induced by LPS. Additionally, DCs treated with STAT3 inhibitor (S3I-201) showed reduced IL-10 production to the same levels observed in DCs treated with WEB2086. The requirement of STAT3 was confirmed in PAFR-KO DCs, since the STAT3 inhibition did not affect IL-10 production by these cells. Our data show an additional molecular mechanism whereby PAFR contributes to IL-10 production in DCs and support the importance of the PAFR activation in DCs phenotype and function.

IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus.

Chronic lymphocytic leukemias (CLLs) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce interleukin 10 (IL-10). The two subsets differ in their levels of anergy, defined by low surface immunoglobulin M levels/signaling capacity, and in their DNA methylation profile, particularly variable in M-CLL. We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL and correlated with anergy. DNA methylation analysis of IL10 locus revealed two previously uncharacterized 'variably methylated regions' (CLL-VMRs1/2) in the gene body, but similarly low methylation in the promoter of both U-CLL and M-CLL. CLL-VMR1/2 methylation was lower in M-CLL than in U-CLL and inversely correlated with IL-10 induction. A functional signal transducer and activator of transcription 3 (STAT3) binding site in CLL-VMR2 was confirmed by proximity ligation and luciferase assays, whereas inhibition of SYK-mediated STAT3 activation resulted in suppression of IL10. The data suggest epigenetic control of IL-10 production. Higher tumor load may compensate the reduced IL-10 production in U-CLL, accounting for clinical immunosuppression in both subsets. The observation that SYK inhibition also suppresses IL-10 provides a potential new rationale for therapeutic targeting and immunological rescue by SYK inhibitors in CLL.

Bone marrow stromal cells attenuate LPS-induced mouse acute liver injury via the prostaglandin E 2-dependent repression of the NLRP3 inflammasome in Kupffer cells

The nucleotide-binding and oligomerization domain-like receptor 3 (NLRP3) inflammasome participates in the pathogenesis of acute liver injury during sepsis. Bone marrow mesenchymal stem cells (BMSCs) attenuate sepsis through prostaglandin E 2 (PGE2) by increasing the interleukin-10 (IL-10) production of macrophages; moreover, NLRP3 inflammasome assembly is effectively regulated by IL-10 during infection. Whether BMSCs have an effect on the activation of the NLRP3 inflammasome and its underlying mechanism is unclear. Administering of BMSCs to mice or KCs after LPS stimulating have improved liver function and reduced activation of NLRP3 inflammasome in KCs. The beneficial effect of BMSCs was enhanced by over-expression of PGE2 and eliminated by silence of PGE2. Additionally, The IL-10 levels in the serum and supernatant were increased by given BMSCs and further increase by PGE2 over-expressed BMSCs, but decreased markedly by PGE2 silenced BMSCs. Furthermore, extracellular signal-regulated kinase 1 (ERK1) inhibitor reduced IL-10 production in KCs and blocked the inhibitory effect of PGE2 on the activation of the NLRP3 inflammasome. Our data reveal a novel mechanism of BMSC-mediated suppression of the activation of KCs through the secretion of PGE2 by BMSCs, which promotes KCs to secrete IL-10, leading to the inhibition of the NLRP3 inflammasome in KCs.

Relationship Between HIV Coinfection, Interleukin 10 Production, and Mycobacterium tuberculosis in Human Lymph Node Granulomas.

Background. Human immunodeficiency virus type 1 (HIV)–infected persons are more susceptible to tuberculosis than HIV–uninfected persons. Low peripheral CD4+ T-cell count is not the sole cause of higher susceptibility, because HIV–infected persons with a high peripheral CD4+ T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV–uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis–associated granulomas.Methods. We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4+ T-cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas.Results. HIV increased M. tuberculosis numbers and reduced CD4+ T-cell counts within granulomas. Peripheral CD4+ T-cell depletion correlated with granulomas that contained fewer CD4+ and CD8+ T cells, less interferon γ, more neutrophils, more interleukin 10 (IL-10), and increased M. tuberculosis numbers. M. tuberculosis numbers correlated positively with IL-10 and interferon α levels and fewer CD4+ and CD8+ T cells. ART reduced IL-10 production.Conclusions. Peripheral CD4+ T-cell depletion correlated with increased M. tuberculosis presence, increased IL-10 production, and other phenotypic changes within granulomas, demonstrating the HIV infection progressively changes these granulomas.

Silencing Triggering Receptors Expressed on Myeloid Cells-1 Impaired the Inflammatory Response to Oxidized Low-Density Lipoprotein in Macrophages.

Atherosclerosis is a chronic progressive inflammatory disease characterized by the accumulation of lipid contents in arterial walls. Previous studies suggest participation of Toll-like receptors (TLRs) in lipid deposition and inflammatory response in vascular wall. The triggering receptor expressed on myeloid cells 1 (TREM-1) is a cell surface receptor of the immunoglobulin superfamily, which amplifies signal transduction of TLR pathway and enhances immune response to microbial infections. The aim of the present study was to investigate the effect of the oxidized low-density lipoprotein (oxLDL) on the expression of the TREM-1, as well as its engagement in proinflammatory cytokine production and foam cell formation in RAW264.7 mice macrophages. oxLDL enhanced TREM-1 and TLR-4, but not TLR-2 gene expression in macrophages; furthermore, silencing TREM-1 expression by short hairpin interfering RNA inhibited lipid phagocytosis and proinflammatory tumor necrosis factor-α (TNF-α) as well as interleukin-6 (IL-6) production in macrophages; moreover, application of synthetic antagonist, LP-17 polypeptide, reduced IL-6 production upon oxLDL stimulation in vitro and in vivo. In conclusion, in macrophages, oxLDL enhanced expression of TREM-1, which amplifies the innate immune response of TLR pathway; activation of TREM-1 contributes to atherogenesis process by enhancing proinflammatory cytokine production and foam cell formation.

Hyperproduction of IL-6 caused by aberrant TDP-43 overexpression in high-fat diet-induced obese mice

Inclusion of Tat-activating regulatory DNA-binding protein-43 (TDP-43) due to hyperphosphorylation or hyperubiquitination is a cause of neurodegenerative disease. Cellular TDP-43 expression is tightly controlled through a negative feedback loop involving its mRNA. Recently, we reported that the TDP-43-mediated sub-nuclear body is an essential site of interleukin-6 (IL-6) pre-mRNA processing. Here we show that mice fed on a high-fat diet exhibit increased TDP-43 expression in the liver and adipose tissue with a prominent increase in IL-6. TDP-43 depletion in vivo reduces IL-6 production in the liver. Overexpression or depletion of TDP-43 in pre-adipose and adipose cells causes reciprocal alteration of IL-6 expression and RNA processing. Our findings provide evidence for a link between homeostasis of TDP-43 expression and the risk of developing obesity.