Nitric oxide released by accessory cells mediates the gastrin-releasing peptide effect on murine lymphocyte chemotaxis.
ABSTRACT Several neuropeptides, including gastrin-releasing peptide (GRP), modulate the immune response, specifically lymphocyte chemotaxis. In the present work the effect of GRP on the chemotaxis of murine lymphocytes from different immune locations in both, total leukocyte populations and populations depleted of adherent cells have been studied. Specificity of the GRP effect on chemotaxis using an antagonist of the GRP receptor, as well as the implication of nitric oxide (NO), using inhibitors of NO synthase and donors of NO, were investigated. The effects of GRP stimulating the chemotaxis of lymphocytes from peritoneum, axillary nodes and spleen and decreasing the chemotaxis from thymus were receptor-specific and disappeared in lymphocytes from populations depleted of adherent cells. NO synthase inhibitors blocked the GRP effect on lymphocyte chemotaxis, and this action was reversed in the presence of l-arginine. Thus, the effect of GRP on murine lymphocyte chemotaxis appears to be mediated by NO secreted by adherent cells.
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ABSTRACT: Aging is accompanied by chronic inflammation and oxidative stress, which lead to a marked impairment of immune function and therefore increased mortality. This study assessed the effect of dietary supplementation, for 15 wk, with 5% and 20% (w/w) of biscuits enriched with nutritional doses of vitamins C and E, zinc, selenium, and beta-carotenes on function and oxidative stress parameters of peritoneal leukocytes from middle-aged, prematurely aging mice (PAM) and non-prematurely aging mice (NPAM). After supplementation we measured leukocyte functions (adherence, chemotaxis, phagocytosis, intracellular reactive oxygen species levels, lymphoproliferation, natural killer activity, and interleukin-2 release), antioxidant defenses (superoxide dismutase, glutathione peroxidase, and reduced glutathione), oxidant compounds (extracellular O(2)(-), glutathione disulfide, glutathione disulfide/reduced glutathione ratio, tumor necrosis factor-alpha, nitric oxide, and prostaglandin E(2)), and lipid and DNA oxidative damage, measured by malondialdehyde and 8-oxo,7,8-dihydro-2'-deoxyguanosine levels, respectively. In general, leukocyte functions were improved and redox homeostasis was restored after intake of antioxidants. In consequence, malondialdehyde and 8-oxo,7,8-dihydro-2'-deoxyguanosine in PAM and NPAM were strikingly decreased after 5% and 20% supplementation (malondialdehyde, P < 0.001 in PAM; P < 0.01 in NPAM after both treatments; 8-oxo,7,8-dihydro-2'-deoxyguanosine, P < 0.01 after 5% supplementation and P < 0.001 after 20% supplementation in PAM and NPAM). Moreover, the effect of the antioxidants was stronger in PAM than in NPAM, and 20% supplementation was more effective than 5%. Our data suggest that improvement of leukocyte function and restoration of redox balance after consumption of adequate levels of antioxidants from adulthood may be useful to attain healthy aging, especially in animals with premature aging.Nutrition 01/2006; 22(7-8):767-77. · 2.86 Impact Factor
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ABSTRACT: Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.Proceedings of the National Academy of Sciences 12/2011; 109(2):547-52. · 9.81 Impact Factor