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1-Methylnicotinamide and nicotinamide: two related anti-inflammatory agents that differentially affect the functions of activated macrophages.

ABSTRACT: 1-Methylnicotinamide (MNA), a major metabolite of nicotinamide (NA), is known to exert anti-inflammatory effects in vivo. Treatment of inflammatory skin diseases by topical application of MNA provides certain advantages over the use of NA. However, in contrast to NA, the molecular mechanisms of the anti-inflammatory properties of MNA are not well known. In this study the influence of exogenous MNA and NA in vivo on the generation of inflammatory mediators by macrophages (Mvarphi) was investigated.Peritoneal Mvarphi of CBA/J mice were activated in vitro with lipopolysaccharide and incubated with MNA or NA. The effect of these compounds on biological functions of Mvarphi was measured by evaluation of the production of reactive oxygen species (ROS) by luminol-dependent chemiluminescence, cytokines and prostaglandin E(2) (PGE(2)) by ELISA, and nitric oxide (NO) by the Griess method. Moreover, the expressions of inducible NO synthase and cyclooxygenase-2 were measured by Western blotting.It was shown that at non-cytotoxic concentrations, NA inhibits the production of a variety of pro-inflammatory agents, such as tumor necrosis factor alpha, interleukin 6, NO, PGE(2), and the generation of ROS. In contrast to NA, exogenous MNA inhibited only the generation of ROS, while its effect on the synthesis of other mediators was negligible.These results indicate that the anti-inflammatory properties of MNA demonstrated previously in vivo do not depend on its capacity to suppress the functions of immune cells, but more likely may be related to its action on vascular endothelium. The authors suggest that the limited permeability for exogenous MNA, in contrast to that for NA, may be responsible for its lack of suppressor activity against Mvarphi.

SUBMITTER: Biedron R

PROVIDER: S-EPMC2766500 | biostudies-other | 2008 Mar-Apr

REPOSITORIES: biostudies-other

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Project description:Defense and protection to multiple harmful stimuli are the inflammation, when is self-amplified and uncontrolled is the basis of the pathogenesis of a wide variety of inflammatory illness. The aim of this study was to evaluate if Petiveria alliacea could attenuate inflammation in a murine model of RAW264 macrophages the involved model and its involved mechanism.The ethanol extract from P. alliacea was precipitated with water and supernatant was used for this study (PW). The anti-inflammatory effects of PW were investigated through evaluating of the production of several cytokines, chemokines, and expression of nuclear factor-kappa B (NF-κB) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Also was determined the ability to decrease the oxidative stress in RAW264.7 cells with carboxy-2',7'-dichloro-dihydro-fluorescein diacetate.PW significantly suppress the secretion of prostaglandin E2, leukotriene C4, interleukin (IL)-1 β, IL-6, IL-10, interferon gamma nitric oxide (NO), inducible NO synthase, IL-1 β, IL-4, in RAW264.7 cells in a dose-dependent manner. In addition, PW also markedly inhibited the transcriptional activity of NF-κB. PW produced significant anti-inflammatory activity through inhibiting the production of inflammatory mediators through the NF-κB inactivation in the LPS-stimulated RAW24.7 cells.PW exerts significant antioxidant and anti-inflammatory activities, and this effect can be attributed in part, to the presence of dibenzyl disulfide, dibenzyl trisulfide pinitol, coumarin, myricetin, glutamyl-S-benzyl cysteine, and petiveriins A and B.Treatment with ethanol extract from Petiveria alliacea which was previously precipitated with water and supernatant (PE) was tested in LPS-stimulated RAW264.7 cells. PE suppressed the level of oxidative stress and the induction of proinflammatory mediators, as PGE2, LTC4, IL-1 ß, IL-6, IL-10, IFN- NO, iNOS, IL-1 ß, IL-4, in RAW264.7 macrophages through NF-B inactivation. These findings suggest that P. alliacea affords promising therapeutic in inflammatory diseases. Abbreviation used: COX-2: Ciclooxigenasa 2; DCFHDA: Carboxy-2',7'-dichloro-dihydro-fluorescein diacetate; DMEM: Dulbecco's modified eagle's medium; FBS: Fetal bovine serum; HSP70: Heat shock protein; IFN-γ: Interferon gamma; IL-1 β: Interleukin 1 β, IL-6: Interleukin 6; IL-10: Interleukin 10; IL-4: Interleukin 4; iNOS: Nitric oxide synthase; KCl: Potassium chloride; LPS: Lipopolysaccharides; LTC4: leukotriene C 4; MgCl2: Magnesium chloride; MTT: 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B-cells or transcriptional activity of nuclear factor-kB; NO: Nitric oxide; PBS: Phosphate-buffered saline; PGE2: Prostaglandin E2, PMSF: Phenylmethylsulfonyl fluoride; PTC: Chloroform extract from Petiveria alliacea; PE: Ethanol extract from Petiveria alliacea; PTH: Hexane extract from Petiveria alliacea; PW: Supernatant of PTE precipitated with water; RAW264.7: Cell line murine macrophages; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor.

Project description:BackgroundAntibody Fc-driven engagement of macrophages is critical for evoking cellular activation and effector functions and influencing tumour-associated macrophage (TAM) recruitment. We previously reported that IgE class antibodies promote restriction of cancer growth in rodent models associated with significant TAM infiltration. However, the human macrophage-associated IgE-Fc Receptor (FcεR) axis remains unexplored. We investigated the effects of anti-tumour IgE stimulation on human macrophage activation.MethodsHuman blood monocyte-differentiated quiescent (M0), classically-(M1) and alternatively-(M2) activated macrophages were crosslinked with IgE and polyclonal antibodies to mimic immune complex formation. We examined surface marker expression, cytokine secretion, protein kinase phosphorylation and gene expression in IgE-stimulated macrophages and IgE antibody-dependent macrophage-mediated cytotoxicity (ADCC) against tumour cells.FindingsA proportion (40%) of M2 and (<20%) M0 and M1 macrophages expressed the high-affinity IgE receptor FcεRI. IgE crosslinking triggered upregulation of co-stimulatory CD80, increased TNFα, IFNγ, IL-1β, IL-12, IL-10, IL-13, CXCL9, CXCL11 and RANTES secretion by M0 and M2 and additionally enhanced MCP-1 by M2 macrophages. IgE-stimulated M1 macrophages retained secretion of pro-inflammatory cytokines. IgE crosslinking enhanced the FcεRI-dependent signalling pathway, including phosphorylation of the Lyn kinase, ERK1/2 and p38 in M2 macrophages and upregulated Lyn gene expression by M1 and M2 macrophages. Anti-tumour IgE engendered ADCC of cancer cells by all macrophage subsets.InterpretationIgE can engage and re-educate alternatively-activated macrophages towards pro-inflammatory phenotypes and prime all subsets to mediate anti-tumour functions. This points to IgE-mediated cascades with potential to activate immune stroma and may be significant in the clinical development of strategies targeting tumour-resident macrophages.

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1-Methylnicotinamide and nicotinamide: two related anti-inflammatory agents that differentially affect the functions of activated macrophages.

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