Release Of Interleukin-1beta Research Articles

Neutrophils Contribute to the Protection Conferred by ArtinM against Intracellular Pathogens: A Study on Leishmania major.

ArtinM, a D-mannose binding lectin from Artocarpus heterophyllus, has immunomodulatory activities through its interaction with N-glycans of immune cells, culminating with the establishment of T helper type 1 (Th1) immunity. This interaction protects mice against intracellular pathogens, including Leishmania major and Leishmania amazonensis. ArtinM induces neutrophils activation, which is known to account for both resistance to pathogens and host tissue injury. Although exacerbated inflammation was not observed in ArtinM-treated animals, assessment of neutrophil responses to ArtinM is required to envisage its possible application to design a novel immunomodulatory agent based on carbohydrate recognition. Herein, we focus on the mechanisms through which neutrophils contribute to ArtinM-induced protection against Leishmania, without exacerbating inflammation. For this purpose, human neutrophils treated with ArtinM and infected with Leishmania major were analyzed together with untreated and uninfected controls, based on their ability to eliminate the parasite, release cytokines, degranulate, produce reactive oxygen species (ROS), form neutrophil extracellular traps (NETs) and change life span. We demonstrate that ArtinM-stimulated neutrophils enhanced L. major clearance and at least duplicated tumor necrosis factor (TNF) and interleukin-1beta (IL-1β) release; otherwise, transforming growth factor-beta (TGF-β) production was reduced by half. Furthermore, ROS production and cell degranulation were augmented. The life span of ArtinM-stimulated neutrophils decreased and they did not form NETs when infected with L. major. We postulate that the enhanced leishmanicidal ability of ArtinM-stimulated neutrophils is due to augmented release of inflammatory cytokines, ROS production, and cell degranulation, whereas host tissue integrity is favored by their shortened life span and the absence of NET formation. Our results reinforce the idea that ArtinM may be considered an appropriate molecular template for the construction of an efficient anti-infective agent.

Dynorphin 1-17 and Its N-Terminal Biotransformation Fragments Modulate Lipopolysaccharide-Stimulated Nuclear Factor-kappa B Nuclear Translocation, Interleukin-1beta and Tumor Necrosis Factor-alpha in Differentiated THP-1 Cells.

Dynorphin 1–17, (DYN 1–17) opioid peptide produces antinociception following binding to the kappa-opioid peptide (KOP) receptor. Upon synthesis and release in inflamed tissues by immune cells, DYN 1–17 undergoes rapid biotransformation and yields a unique set of opioid and non-opioid fragments. Some of these major fragments possess a role in immunomodulation, suggesting that opioid-targeted therapeutics may be effective in diminishing the severity of inflammatory disorders. This study aimed to examine the immunomodulatory effects of DYN 1–17 and major N-terminal fragments found in the inflammatory environment on nuclear factor-kappaB/p65 (NF-κB/p65) nuclear translocation and the release of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) from lipopolysaccharide (LPS)-stimulated, differentiated THP-1 cells. The results demonstrate that NF-κB/p65 nuclear translocation was significantly attenuated following treatment with DYN 1–17 and a specific range of fragments, with the greatest reduction observed with DYN 1–7 at a low concentration (10 nM). Antagonism with a selective KOP receptor antagonist, ML-190, significantly reversed the inhibitory effects of DYN 1–17, DYN 1–6, DYN 1–7 and DYN 1–9, but not other DYN 1–17 N-terminal fragments (DYN 1–10 and 1–11) on NF-κB/p65 nuclear translocation. DYN 1–17 and selected fragments demonstrated differential modulation on the release of IL-1β and TNF-α with significant inhibition observed with DYN 1–7 at low concentrations (1 nM and 10 pM). These effects were blocked by ML-190, suggesting a KOP receptor-mediated pathway. The results demonstrate that DYN 1–17 and certain N-terminal fragments, produced in an inflamed environment, play an anti-inflammatory role by inhibiting NF-κB/p65 translocation and the subsequent cytokine release through KOP receptor-dependent and independent pathways.

The effect of 17β-estradiol on gene expression of calcitonin gene-related peptide and some pro-inflammatory mediators in peripheral blood mononuclear cells from patients with pure menstrual migraine.

The neuropeptide calcitonin gene-related peptide (CGRP) has long been postulated to play an integral role in the pathophysiology of migraine. Earlier studies showed that CGRP can stimulate the synthesis and release of nitric oxide (NO) and cytokines from trigeminal ganglion glial cells. The purpose of this study was to determine the effect of 17β-estradiol in regulation of CGRP expression, inducible nitric oxide synthase (iNOS) activity, and NO and interleukin-1beta (IL-1β) release in cultured peripheral blood mononuclear cells (PBMCs) from patients with pure menstrual migraine and healthy individuals. This study was performed on twelve patients with pure menstrual migraine and twelve age-and sex-matched healthy individuals. PBMCs treated with 17β-estradiol for 24 hr at physiological and pharmacological doses. Gene expression was evaluated by real time-PCR. CGRP and IL-1β proteins in culture supernatant were determined by ELISA method. Activity of iNOS in PBMCs and total nitrite in the culture supernatant were measured by colorimetric assays. Treatment with 17β-estradiol had a biphasic effect on expression of CGRP. We found that 17β-estradiol treatment at pharmacological dose significantly increases mRNA expression of CGRP in both groups (P<0.001), whereas at physiological dose it could significantly decrease CGRP mRNA expression (P<0.001), CGRP protein levels, IL-1β release, NO production and iNOS activity only in patient groups (P<0.05). Collectively, it appears that 17β-estradiol can exert protective effect on decrease of inflammation in migraine via decrease in levels of CGRP, IL-1β and iNOS activity; however, more studies are necessary in this regard.

Comparison of the effects of hypolipidemic treatment on monocyte proinflammatory cytokine release in men and women with type 2 diabetes and atherogenic dyslipidemia.

Statins and fibrates reduce monocyte release of proinflammatory cytokines, but it remains unknown whether this effect is sex dependent. We retrospectively analysed age-, weight-, and lipid-matched populations of type 2 diabetic patients of both sexes, who, because of atherogenic dyslipidaemia, were treated with simvastatin (40 mg daily), fenofibrate (200 mg daily), or simvastatin plus fenofibrate. Monocyte release of tumour necrosis factor α (TNF-α), inteleukin-1β, interleukin-6, and monocyte chemoattractant protein-1 (MCP-1), as well as circulating levels of high-sensitivity C-reactive protein (hsCRP) and free fatty acids (FFA) were assessed separately for men and women before and after 12 weeks of treatment. Baseline monocyte release of TNF-α, interleukin-1β, interleukin-6, and MCP-1, as well as plasma hsCRP and FFA levels were comparable in both sexes. Simvastatin, fenofibrate, and simvastatin/fenofibrate combination therapy reduced monocyte release of TNF-α, inteleukin-1β, interleukin-6, and MCP-1, with no difference between the treatment groups. The impact of simvastatin and fenofibrate administered alone on monocyte cytokine release and systemic inflammation did not differ between the men and women. The effect of simvastatin/fenofibrate combination therapy on monocyte release of interleukin-6 and MCP-1 was more pronounced in the male population. The impact of simvastatin administered together with fenofibrate on TNF-α, interleukin-1β, and hsCRP was also stronger in the men than in the women, but the difference did not reach the level of significance. The obtained results suggest that sex differences determine the strength of the monocyte-suppressing effect of simvastatin/ /fenofibrate combination therapy in type 2 diabetic patients with atherogenic dyslipidaemia.

Ozone Exposure Initiates a Sequential Signaling Cascade in Airways Involving Interleukin-1Beta Release, Nerve Growth Factor Secretion, and Substance P Upregulation

Previous studies demonstrated that interleukin-1β (IL-1β) and nerve growth factor (NGF) increase synthesis of substance P (SP) in airway neurons both after ozone (O3) exposure and by direct application. It was postulated that NGF mediates O3-induced IL-1β effects on SP. The current study specifically focused on the influence of O3 on IL-1β, NGF, and SP levels in mice bronchoalveolar lavage fluid (BALF) and whether these mediators may be linked in an inflammatory-neuronal cascade in vivo. The findings showed that in vivo O3 exposure induced an increase of all three proteins in mouse BALF and that O3-induced elevations in both NGF and SP are mediated by the inflammatory cytokine IL-1β. Further, inhibition of NGF reduced O3 induced increases of SP in both the lung BALF and lung tissue, demonstrating NGF serves as a mediator of IL-1β effects on SP. These data indicate that IL-1β is an early mediator of O3-induced rise in NGF and subsequent SP release in mice in vivo.

Hepatotoxicants induce cytokine imbalance in response to innate immune system

In recent years, attention has been paid to innate immune systems as mechanisms to initiate or promote drug-induced liver injury (DILI). Kupffer cells are hepatic resident macrophages and might be involved in the pathogenesis of DILI by release of pro- and anti-inflammatory mediators such as cytokines, chemokines, reactive oxygen species, and/or nitric oxides. The purpose of this study was to investigate alterations in mediator levels induced by hepatotoxic compounds in isolated Kupffer cells and discuss the relation between balance of each cytokine or chemokine and potential of innate immune-mediated DILI. Primary cultured rat Kupffer cells were treated with hepatotoxic (acetaminophen, troglitazone, trovafloxacin) or non-hepatotoxic (pioglitazone, levofloxacin) compounds with or without lipopolysaccharide (LPS). After 24 hr treatment, cell supernatants were collected and various levels of mediators released by Kupffer cells were examined. Although hepatotoxicants had no effect on the LPS-induced tumor necrosis factor-alpha (TNF-α) secretion, they enhanced the release of pro-inflammatory cytokine interleukin-1 beta (IL-1β) and suppressed the anti-inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10) induced by LPS. These cytokine shifts were not associated with switching the phenotypes of M1 and M2 macrophages in Kupffer cells. In conclusion, the present study suggested that the levels of some specific cytokines are affected by DILI-related drugs with LPS stimulation, and imbalance between pro- and anti-inflammatory cytokines, induced by the up-regulation of IL-1β and the down-regulation of IL-6 or IL-10, plays a key role in innate immune-mediated DILI.

Ribavirin shows immunomodulatory effects on activated microglia

Ribavirin (RBV) is synthetic purine nucleoside analogue, licensed as anti-viral drug that displays immunomodulatory actions on various immune cells. Our previous ex vivo studies have demonstrated immunosuppressive effects of RBV on reactive T-lymphocytes in experimental autoimmune encephalomyelitis. Here, we examined the effects of RBV on inflammatory response of microglia. RBV potency to down-regulate microglia inflammatory response was assessed by measuring microglia cell body size, and the production of nitric oxide (NO) and pro- and anti-inflammatory cytokines. RBV exerted cytotoxic effects on LPS-stimulated microglia, leaving non-stimulated microglia unaffected. The exposure of activated microglia to RBV led to: decrease in the level of NO as a result of decreased cell number, lower average cell surface, the reduction of membrane ruffling, the suppression of interleukin-6 release and promoted interleukin-10 production. On the other hand, RBV promoted LPS-induced interleukin-1 beta release. Our results imply that RBV is a complex immunomodulator showing both anti- and pro-inflammatory effects on activated microglia.

Inflammation-reactive astrocytes can be restored with a three drug combination

Abstract Aims In inflammation-reactive astrocytes the cell parameters, Ca2+ signalling, Na+ transporters, cytoskeleton, and release of proinflammatory cytokines are affected. We want to re-establish these parameters with agents, which might have a potential to restore the cells back to a normal non-inflammatory level. Methods Astrocytes in primary cultures were incubated with lipopolysaccharide (LPS) (10 ng/ml) for 24 h to become inflammation-reactive. Different parameters were analysed to verify this inflammation: Ca2+ signalling, Na+/K+-ATPase expression, actin filament organization, and interleukin-1beta release (IL-1β). Results We have used an opioid agonist, endomorphin-1, that stimulates the Gi/o protein of the μ-opioid receptor, an opioid antagonist, naloxone, that inhibits the Gs protein of the μ-opioid receptor in ultralow concentrations, and an anti-epileptic agent, levetiracetam, that counteracts the release of IL-1β. The combination of these three agents managed to activate the Gi/o protein and Na+/K+-ATPase activity, inhibit the Gs protein, and decrease the release of IL-1β. The disorganized actin filaments were restored. Conclusions The findings that the important cell parameters in astrocytes were restored back to their normal non-inflammatory state after the cells were treated with the inflammatory agent LPS could be of clinical significance. It may be useful for the treatment of neuroinflammation and also maybe of long-term pain. The astrocyte networks play a significant role and therefore a well-working intercellular Ca2+ signalling is of utmost importance. Significance These findings put new potential drug regimens towards treatment of neuroinflammation and long-term pain into focus.

P2X7 receptor–Pannexin1 interaction mediates stress‐induced interleukin‐1 beta expression in human periodontal ligament cells

Pannexin 1 (Panx1) has been found to form nonjunctional hemichannels. It is also proposed to combine with the P2X7 receptor, forming a complex involved in adenosine triphosphate (ATP)-induced interleukin-1beta (IL-1β) release in macrophages. Previously, we reported that mechanical stress induced IL-1β expression via the ATP/P2X7 receptor-dependent pathway in human periodontal ligament (HPDL) cells and that ATP was released through the connexin 43 (Cx43) hemichannel. In the present work, we examined the role of Panx1 in stress-induced IL-1β induction in HPDL cells. Cultured HPDL cells were treated with compressive loading or ATP to stimulate IL-1β expression. Inhibitors, antagonists and the small interfering RNA technique were used to investigate the involvement of Panx1 in IL-1β induction. Co-immunoprecipitation (Co-IP) and immunostaining were used to determine the association of Panx1 with the P2X7 receptor. The IL-1β release mechanism was analyzed using inhibitors. Blocking Panx1 significantly decreased ATP release, as well as IL-1β up-regulation, upon stimulation with stress or ATP. Co-IP revealed the association of Panx1 and the P2X7 receptor in HPDL cells, which was increased in response to mechanical loading. Pretreatment with vesicular trafficking inhibitors significantly reduced the amount of IL-1β released from stimulated cells, suggesting that IL-1β might be released through vesicles. We clearly illustrated the contribution of Panx1 in ATP release, as well as in IL-1β induction in HPDL cells. The association of Panx1 and the P2X7 receptor might be required for IL-1β induction, and their possible novel role in IL-1β vesicular release was indicated.

Paeonol attenuates inflammation-mediated neurotoxicity and microglial activation.

Chronic activation of microglial cells endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. The root of Paeonia lactiflora Pall has been considered useful for the treatment of various disorders in traditional oriental medicine. Paeonol, found in the root of Paeonia lactiflora Pall, has a wide range of pharmacological functions, including anti-oxidative, anti-inflammatory and neuroprotective activities. The objective of this study was to examine the efficacy of paeonol in the repression of inflammation-induced neurotoxicity and microglial cell activation. Organotypic hippocampal slice cultures and primary microglial cells from rat brain were stimulated with bacterial lipopolysaccharide. Paeonol pretreatment was performed for 30 minutes prior to lipopolysaccharide addition. Cell viability and nitrite (the production of nitric oxide), tumor necrosis factor-alpha and interleukin-1beta products were measured after lipopolysaccharide treatment. In organotypic hippocampal slice cultures, paeonol blocked lipopolysaccharide-related hippocampal cell death and inhibited the release of nitrite and interleukin-1beta. Paeonol was effective in inhibiting nitric oxide release from primary microglial cells. It also reduced the lipopolysaccharide-stimulated release of tumor necrosis factor-alpha and interleukin-1β from microglial cells. Paeonol possesses neuroprotective activity in a model of inflammation-induced neurotoxicity and reduces the release of neurotoxic and proinflammatory factors in activated microglial cells.

AB0613 Omega-3 polyunsaturated fatty acids for the treatment of rheumatoid arthritis: A meta-analysis

BackgroundOmega-3 polyunsaturated fatty acids (PUVAs) may lead to a reduction of pain and inflammation via competitively inhibiting the production of PGE2 and LTB4 and inhibiting the release of interleukin-1 beta...

Profile of certolizumab and its potential in the treatment of psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis (PsO). PsA could be considered an enthesal disease because of the link between mechanical stress (entheses) and immunologically active tissue (synovium). Evidence of efficacy of anti-tumor necrosis factor alpha (TNF-α) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment. Certolizumab pegol (CZP) is a polyethylene glycolylated (PEGylated) Fab’ fragment of a humanized monoclonal antibody that binds and neutralizes human TNF-α. The PEG moiety of the Fab fragment, markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti-TNF-α agents tested for the treatment of Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA. In contrast to other anti-TNF-α agents, CZP did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the anti-TNF-α efficacy in Crohn’s disease. As CZP, infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may be relevant for drug efficacy. Due to these characteristics, it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis. This drug can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.

Interleukin-1-mediated diseases

Interleukin-1 (IL-1)-mediated diseases are caused by an inappropriately high production and release of IL-1 beta which results in a multitude of symptoms, e.g. arthritis, exanthema, conjunctivitis, serositis, fever and loss of hearing. If IL-1-mediated diseases remain unrecognized or are recognized and treated too late, long-term complications, such as amyloidosis may occur. In recent years the diagnostic and therapeutic options with respect to IL-1-mediated diseases have drastically improved. These diseases often manifesting in childhood can now be treated with monoclonal antibodies against IL-1 or with IL-1 receptor antagonists. Increased IL-1 secretion does not only play a role in relatively rare hereditary diseases, such as cryopyrin-associated periodic fever syndromes or familial Mediterranean fever but also in widespread diseases, such as gout or type 2 diabetes. This article will focus on pathogenic, diagnostic and therapeutic aspects of IL-1-mediated inflammatory diseases.

Therapeutic Attenuation of Neuroinflammation and Apoptosis by Black Tea Theaflavin in Chronic MPTP/Probenecid Model of Parkinson’s Disease

Neuroinflammation and apoptosis in the dopaminergic neurons of substantia nigra play an important role in the pathogenesis of experimental and clinical Parkinson's disease (PD). This study focused on the possible anti-inflammatory and anti-apoptotic effects of theaflavin (TF), a black tea polyphenol against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. C57BL/6 male mice were treated with 10 doses of MPTP (25mg/kg, s.c.) and probenecid (250mg/kg, i.p.) for 3.5days interval. TF (10mg/kg) was administered 1h prior to the administration of MPTP for 35days of experimental period. MPTP/p treatment upregulates the release of interleukin-1beta, IL-6, tumor necrosis factor-alpha, IL-10, glial fibrillary acidic protein and Bax, and downregulates anti-apoptotic marker Bcl-2. Oral treatment of black tea polyphenol TF significantly attenuates MPTP-induced neuroinflammation as well as apoptosis. Behavioral studies (catalepsy and akinesia) were carried out to confirm these molecular studies. The results demonstrate that TF mediated its neuroprotection against chronic MPTP-induced toxicity through the involvement of multiple molecular events. It was concluded that TF may provide a precious therapeutic strategy for the treatment of progressive neurodegenerative disease such as PD in future.

IMPACT OF NLRP3 INFLAMMASOME ON THE DEVELOPMENT OF HYPERTENSION AND RENAL AND CARDIAC HYPERTROPHY IN 2K1C AND DOCA/SALT MICE

NLRP3 inflammasome is formed by NLRP3, the adaptor ASC, and caspase-1, functions as a sensor of danger signals and triggers processing and release of interleukin-1beta (IL-1β). Recent animal studies demonstrate that NLRP3 inflammasome promotes renal inflammation. However, little is known on the role of NLRP3 in hypertension. We have investigated the effect of NLRP3 inflammasome on blood pressure, plasma renin activity and concentration (PRA and PRC), renal and cardiac hypertrophy in NALP3 and ASC deficient mice on which the two-kidney, one clip (2K1C) and the deoxycorticosterone-acetate (DOCA)/salt models were applied. MBP, PRA, PRC, and HW/BW were significantly increased at week 12 in WT-2K1C mice compared to the sham. Neither NLAP3-KO nor ASC-KO 2K1C treated mice developed hypertension and had lower circulating levels of PRA and PRC and serum amyloid A (SAA) and IL6 compared to the control. RNA levels of SAA, NLRP3, IL1β and IL1α were increased in the ischemic kidney in C57BL/6J mice. Administration of anti-IL1β antibody to the WT mice attenuated the increases of blood pressure and renin in 2K1C mice. With chronic administration of DOCA/salt, MBPs in both NLRP3-KO and WT mice were comparable and not significantly increased compared to tap water group. PRA and PRC in both NALP3-KO and WT mice were significantly suppressed by DOCA/salt. HW/BW and KW/BW in both DOCA/salt treated NALP3-KO and WT mice were significantly increased. DOCA/salt induced hypokalemia was comparable between Nlrp3 KO and WT groups. However, the heart and kidney index in DOCA/salt NLRP3-KO mice was significantly lower than that in DOCA/salt WT mice. Our data show that NLRP3 mediated IL1β is linked to development of renovascular hypertension and suggest that a novel target for the treatment of hypertension. The results also implicate that NLRP3 contributes to the development of cardiac and renal hypertrophy independently of blood pressure in the DOCA/salt model.

The effect of diffusion hardened oxidized zirconium wear debris on cell viability and inflammation-An in vitro study

Wear debris generation in total joint replacement remains a concern because of its association with aseptic loosening, osteolysis, and ultimately implant failure. In a quest to develop new implant materials with reduced wear and improved biocompatibility a new composition of oxidized Zr2.5Nb alloy; diffusion hardened oxidized zirconium (DHOxZr) has been developed. In this study, we have determined the in vitro biocompatibility of the wear debris of this new composition and compared it to wear debris particles of Ti6Al4V, Cobalt, and CoCr. The cytotoxicity of these particles on fibroblast-like cells (L929) and osteoblast-like cells (SaOS2) was assessed using lactate dehydrogenase and DNA quantification assays. The inflammatory response to these particles was assessed by release of interleukin-1 beta and tumor necrosis factor from macrophage-like cells. The results showed that wear debris generated from DHOxZr was less cytotoxic and elicited a reduced inflammatory response as compared to that of Cobalt or CoCr and might therefore offer a benefit as a joint prosthesis.

Enniatin B-induced cell death and inflammatory responses in RAW 267.4 murine macrophages

The mycotoxin enniatin B (EnnB) is predominantly produced by species of the Fusarium genera, and often found in grain. The cytotoxic effect of EnnB has been suggested to be related to its ability to form ionophores in cell membranes. The present study examines the effects of EnnB on cell death, differentiation, proliferation and pro-inflammatory responses in the murine monocyte–macrophage cell line RAW 264.7. Exposure to EnnB for 24h caused an accumulation of cells in the G0/G1-phase with a corresponding decrease in cyclin D1. This cell cycle-arrest was possibly also linked to the reduced cellular ability to capture and internalize receptors as illustrated by the lipid marker ganglioside GM1. EnnB also increased the number of apoptotic, early apoptotic and necrotic cells, as well as cells with elongated spindle-like morphology. The Neutral Red assay indicated that EnnB induced lysosomal damage; supported by transmission electron microscopy (TEM) showing accumulation of lipids inside the lysosomes forming lamellar structures/myelin bodies. Enhanced levels of activated caspase-1 were observed after EnnB exposure and the caspase-1 specific inhibitor ZYVAD-FMK reduced EnnB-induced apoptosis. Moreover, EnnB increased the release of interleukin-1beta (IL-1β) in cells primed with lipopolysaccharide (LPS), and this response was reduced by both ZYVAD-FMK and the cathepsin B inhibitor CA-074Me.In conclusion, EnnB was found to induce cell cycle arrest, cell death and inflammation. Caspase-1 appeared to be involved in the apoptosis and release of IL-1β and possibly activation of the inflammasome through lysosomal damage and leakage of cathepsin B.

External Apical Root Resorption and the Release of Interleukin-1 Beta in the Gingival Crevucular Fluid Treated by a Self-Ligating System

External Apical Root Resorption and the Release of Interleukin-1 Beta in the Gingival Crevucular Fluid Treated by a Self-Ligating System

High-density lipoprotein prevents SAA-induced production of TNF-α in THP-1 monocytic cells and peripheral blood mononuclear cells

In this study, we evaluated whether human serum and lipoproteins, especially high-density lipoprotein (HDL), affected serum amyloid A (SAA)-induced cytokine release. We verified the effects of SAA on THP-1 cells in serum-free medium compared to medium containing human serum or lipoprotein-deficient serum. SAA-induced tumour necrosis factor-alpha (TNF-α) production was higher in the medium containing lipoprotein-deficient serum than in the medium containing normal human serum. The addition of HDL inhibited the SAA-induced TNF-α release in a dose-dependent manner. This inhibitory effect was specific for HDL and was not affected by low-density lipoprotein or very low-density lipoprotein. In human peripheral blood mononuclear cells, the inhibitory effect of HDL on TNF-α production induced by SAA was less pronounced. However, this effect was significant when HDL was added to lipoprotein-deficient medium. In addition, a similar inhibitory effect was observed for interleukin-1 beta release. These findings confirm the important role of HDL and support our previous hypothesis that HDL inhibits the effects of SAA during SAA transport in the bloodstream. Moreover, the HDL-induced reduction in the proinflammatory activity of SAA emphasizes the involvement of SAA in diseases, such as atherosclerosis, that are characterized by low levels of HDL.

Methyl-1-hydroxy-2-naphthoate, a novel naphthol derivative, inhibits lipopolysaccharide-induced inflammatory response in macrophages via suppression of NF-κB, JNK and p38 MAPK pathways

The anti-inflammatory effect of methyl-1-hydroxy-2-naphthoate (MHNA), a novel naphthol derivative, was evaluated in the lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages. The release of nitric oxide (NO), interleukin-1beta (IL-1β) and interleukin-6 (IL-6) were detected by the Griess reagent and ELISA methods. The protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were examined by Western blotting. The mRNA expressions of IL-1β, IL-6, iNOS and COX-2 were determined by real-time PCR. Activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) pathways were detected by Western blotting, reporter gene assay and electrophoretic mobility shift assay. MHNA significantly inhibited the release of NO, IL-1β and IL-6 as well as the protein expression of iNOS and COX-2 in LPS-stimulated macrophages. It also inhibited the mRNA expression of iNOS, COX-2, IL-1β and IL-6. Further studies indicated that MHNA inhibited LPS-induced increases in NF-κB DNA-binding activity and NF-κB transcriptional activity as well as IκB-α degradation and NF-κB translocation in a dose-dependent manner. Meanwhile, the activation of p38 MAPK and c-Jun N-terminal kinases (JNK) induced by LPS were decreased by MHNA. MHNA inhibits the LPS-induced inflammatory response in murine macrophages via suppression of NF-κB and MAPKs signaling pathways activation.