RESUMEN
CD40 plays dual immunoregulatory roles in Leishmania major infection and tumor regression. The functional duality emerges from CD40-induced reciprocal p38MAPK and ERK-1/2 phosphorylations. Because phosphotyrosine-based signaling in hematopoietic cells is regulated by the phosphotyrosine phosphatase SHP-1, which is not implied in CD40 signaling, we examined whether SHP-1 played any roles in CD40-induced reciprocal signaling and anti-leishmanial function. We observed that a weaker CD40 stimulation increased SHP-1 activation. ERK-1/2 inhibition or p38MAPK overexpression inhibited CD40-induced SHP-1 activation. An ultra-low-dose, CD40-induced p38MAPK phosphorylation was enhanced by SHP-1 inhibition but reduced by SHP-1 overexpression. A reverse profile was observed with ERK-1/2 phosphorylation. SHP-1 inhibition reduced syk phosphorylation but increased lyn phosphorylation; syk inhibition reduced but lyn inhibition enhanced CD40-induced SHP-1 phosphorylation. Corroborating these findings, in L. major-infected macrophages, CD40-induced SHP-1 phosphorylation increased and SHP-1 inhibition enhanced CD40-induced p38MAPK activation and inducible NO synthase expression. IL-10 enhanced SHP-1 phosphorylation and CD40-induced ERK-1/2 phosphorylation but reduced the CD40-induced p38MAPK phosphorylation, whereas anti-IL-10 Ab exhibited reverse effects on these CD40-induced functions, identifying IL-10 as a crucial element in the SHP-1-MAPK feedback system. Lentivirally overexpressed SHP-1 rendered resistant C57BL/6 mice susceptible to the infection. Lentivirally expressed SHP-1 short hairpin RNA enhanced the CD40-induced L. major parasite killing in susceptible BALB/c mice. Thus, we establish an SHP-1-centered feedback system wherein SHP-1 modulates CD40-induced p38MAPK activation threshold and reciprocal ERK-1/2 activation, establishing itself as a critical regulator of CD40 signaling reciprocity and mechanistically re-emphasizing its role as a potential target against the diseases where CD40 is involved.
Asunto(s)
Antígenos CD40/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Macrófagos/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/inmunología , Animales , Activación Enzimática/inmunología , Interleucina-10/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Leishmaniasis Cutánea/patología , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Proteína Quinasa 3 Activada por Mitógenos/inmunología , Óxido Nítrico Sintasa de Tipo II , Fosforilación/inmunología , Proteínas Tirosina Quinasas/inmunología , Quinasa Syk , Proteínas Quinasas p38 Activadas por Mitógenos/inmunologíaRESUMEN
Hyperosmolar food causes atherosclerosis. Hyperosmolal food hypothesis encompasses all the factors involved under one heading and, that is, the generation of heat in the body. The involvement of cigarette smoking is obvious. High glycemic index food and diabetes result in high levels of blood glucose, which raises the core body temperature. The ingestion of hyperosmolal salt, glucose, and amino acids singularly or synergistically raise the core body temperature, forcing abdominal aorta to form an insulation wall of fatty material causing atherosclerotic plaques. The osmolarity of food, that is glucose, salt, and amino acids is reduced when water is ingested with food. The incidence of atherosclerosis goes down with increasing intake of water.
Asunto(s)
Evolución Biológica , Insectos/genética , Animales , Biología Computacional , Genoma de los Insectos , Hibridación Genética , Insectos/clasificación , Insectos/crecimiento & desarrollo , Larva/genética , Larva/crecimiento & desarrollo , Metamorfosis Biológica/genética , Modelos Genéticos , Biología MolecularRESUMEN
T cells regulate the immune responses to pathogens and autoantigens. The immune responses are tolerizing or anti-inflammatory against autoantigens but are inflammatory against pathogens and allografts. Such contradictory immune responses have been attributed to two counteracting effector cell types or to two counterregulatory sets of molecules: cell-surface expressed or secreted. By contrast, recent reports suggest that CD40, a co-stimulatory molecule on antigen-presenting cells, is a crucial controller of these counteractive immune responses, and emphasize reciprocal inhibition as an essential feature of biological responses. The molecular mechanism of such reciprocity in CD40 functions is the basis of immunotherapy in many diseases.