The nuclear receptor related 1 protein (Nurr1) is a member of the orphan nuclear hormone receptor family whose expression has been associated with several inflammatory diseases. Macrophages are key regulators of the inflammatory processes, yet information about the role of Nurr1 in human macrophages is limited. In the present study we examined the expression and activity of Nurr1 in steady state and activated human monocyte-derived macrophages. Pro- and anti-inflammatory macrophages were derived in vitro by culture of blood monocytes with the hematopoietic cytokines GM-CSF and M-CSF, respectively. Nurr1 expression was predominant in macrophages with a pro-inflammatory phenotype. Accordingly, its expression was induced by a variety of inflammatory stimuli such as TLR-2, -3 and -4 ligands, TNF, IFN-β, and IL-4. Pro-inflammatory macrophages exposed to the Nurr1 agonist C-DIM12 decreased their production of IL-1β, IL-6, and reactive oxygen species. Conversely, Nurr1 deficient macrophages produced enhanced levels of IL-6. Mechanistically, Nurr1 agonists partially abrogated the activation of the NF-κB signaling pathway in pro-inflammatory macrophages exposed to LPS, rendering cells with a lower rate of NF-κB p65 nuclear translocation. These results suggest that Nurr1 expression is linked with the pro-inflammatory phenotype of human macrophages where it may constitute a brake to attenuate the synthesis of inflammatory mediators. Supported by grants from Secretaria de Educación Pública-Consejo Nacional de Ciencia y Tecnología (SEP-CONACYT, #A1-S-9430)
The peripheral repertoire of CD4 1 T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD41 T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4 1 lymphocytes activated by dendritic cells (DCs) presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells (Tmem) from primary effectors activated with mature autologous DCs plus interleukin (IL)-2 (Tm auto ), simulating the circumstances of an active immune response, or allogeneic DCs (Tm allo ). Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors (demonstrated by CD25 downregulation) particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tm auto and Tm allo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tm allo were closely related to conventional memory lymphocytes based on Erk-1/2 activation, whereas Tm auto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD41 T lymphocytes recognizing self-peptides in the setting of strong costimulation.
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