RESUMO
DDT, a persistent organic pollutant, remains affecting human health worldwide. DDT and its most persistent metabolite (p,p'-DDE) negatively affect the immune response regulation and mechanisms involved in protecting against pathogens Such metabolite decreases the capability to limit intracellular growth of Mycobacterium microti and yeast. However, the effect on unstimulated (M0) and anti-inflammatory macrophages (M2) has been evaluated scanty. Herein, we evaluated the impact of p,p'-DDE at environmentally relevant concentrations (0.125, 1.25, 2.5, and 5 µg/mL) on bone marrow-derived macrophages stimulated with IFNγ+LPS to M1 or with IL-4 +IL-13 to M2. Thus we study whether the p,p'-DDE induces M0 to a specific phenotype or modulates activation of the macrophage phenotypes and explains, at least partly, the reported effects of p,p'-DDE on the M1 function. The p,p'-DDE did not affect the cell viability of M0 or the macrophage phenotypes. In M1, the p,p'-DDE decreased NOâ¢- production and IL-1ß secretion, but increasing cellular ROS and mitochondrial O2â¢-, but did not alter iNOS, TNF-α, MHCII, and CD86 protein expression nor affect M2 markers arginase activity, TGF-ß1, and CD206; p,p'-DDE, did not affect marker expression in M0 or M2, supporting that its effects on M1 parameters are not dependent on M0 nor M2 modulation. The decreasing of NOâ¢- production by the p,p'-DDE without altering iNOS levels, Arginase activity, or TNF-α, but increasing cellular ROS and mitochondrial O2 suggests that p,p'-DDE interferes with the iNOS function but not with its transcription. The p,p'-DDE decreasing of IL-1ß secretion, without any effect on TNF-α, suggest that an alteration of specific targets involved in IL-1ß secretion may be affected and related to ROS induction. The p,p'-DDE effect on iNOS function and the IL-1ß secretion process, as the NLRP3 activation, deserves further study.
Assuntos
Diclorodifenil Dicloroetileno , Macrófagos , Animais , Humanos , Camundongos , Arginase/genética , Arginase/metabolismo , Arginase/farmacologia , DDT/metabolismo , DDT/farmacologia , Diclorodifenil Dicloroetileno/toxicidade , Diclorodifenil Dicloroetileno/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
Lead (Pb) is a ubiquitous toxic metal that decreases resistance to infections, in which the macrophages have an essential role. Pb adverse effects on nitric oxide (NO-) production and variable effects on inflammatory cytokines in activated macrophages have been reported, but no effects have been reported in anti-inflammatory macrophages. We studied Pb (0.03-6 µg/dL equivalent to 0.014-2.89 µM) effects on the function of bone marrow-derived macrophages (BMDM) induced to either inflammatory or anti-inflammatory phenotypes, with LPS + IFNγ or IL-4+IL-13, respectively, and whether these effects are related. Pb did not induce cytotoxicity at any concentration in both macrophage phenotypes. In inflammatory BMDM, Pb (6 µg/dL) inhibited NO- production without affecting inducible nitric oxide synthase (iNOS) levels or basal arginase activity. At 3 and 6 µg/dL, Pb enhanced the major histocompatibility complex class II (MHC II) membrane expression but did not modify CD86 expression, TNFα, or IL-1ß production and secretion. In anti-inflammatory BMDM, Pb did not alter arginase activity, but at 3 and 6 µg/dL, increased TGF-ß1 and mannose receptor expression. Results showed that environmentally relevant concentrations of Pb alter functional outcomes or phenotypic markers of anti-inflammatory for the first time. The Pb effects on the inflammatory macrophages are not dependent on negative feedback resulting from the Pb effect on the anti-inflammatory phenotype. The Pb affected only some molecules or specific pathways related to both phenotypes. These effects could be related to Pb effects on immune defense against intracellular pathogens and allergy susceptibility.
Assuntos
Mediadores da Inflamação/metabolismo , Chumbo/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Fenótipo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Chumbo/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The impact of pregnancy hypertension in the offspring endothelia remains unknown. We evaluated the transcriptional expression of four genes that participate in the process of endothelial dysfunction using umbilical vein endothelial cell cultures (HUVEC) from healthy pregnant women (PW) and those with hypertensive disorders (HD). The cytochrome P450 1A1 (CYP1A1), gluthathione S-transferase subtype T1 (GSTT1), interleukin 6 (IL-6) and 8 (IL-8) mRNA and IL-6 protein levels were assessed. IL-6 and IL-8 transcripts were significantly reduced in HUVEC obtained from HD women. Our results suggest that a hypertensive environment in utero modifies the transcriptional expression of key inflammatory molecules in the newborn.