Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages.
ABSTRACT Vitamin A and its metabolites, e.g., all trans-retinoic acid (atRA) and 9-cis-retinoic acid have attracted considerable attention as compounds that have a broad range of immune modulating effects on both humoral and cellular immune responses. The cellular and molecular mechanisms that underlie the effects of retinoids on the immune system remain to be more clearly defined. These immune modulating effects of atRA may be mediated by cytokines elaborated by monocytes and other cell types. To further understand the mechanism(s) by which retinoids affect the immune response, we examined the effects of atRA on several proinflammatory and immune modulating cytokines produced by monocytes. The effects of atRA on LPS-induced mRNA expression of IL-10, IL-12p40, TNF-alpha, IL-18, and TGF-beta in the THP-1 monocyte/macrophage cell line and in cord blood mononuclear cells were measured by competitive RT-PCR. The ELISPOT was employed to evaluate IL-10 and TNF-alpha protein production enumerating the number of IL-10 and TNF-alpha producing cells. The addition of atRA to cell cultures potentiated the LPS-induced IL-10 mRNA expression and the number of IL-10 secreting cells from THP-1 cells and cord blood mononuclear cells. In contrast, the addition of atRA inhibited the LPS-induced TNF-alpha and IL-12p40 mRNA expression, and the number of ELISPOT positive cells for TNF-alpha. atRA did not change the LPS-induced mRNA expression of IL-18 and TGF-beta. These results suggest that atRA may have multiple effects on LPS-induced monocyte/macrophage derived cytokines. While atRA downregulated the proinflammatory cytokines, e.g., IL-12 and TNF-alpha, the production of an immune modulating cytokine, IL-10 was enhanced by atRA. The effects of atRA on these cytokines may play an important role in the modulation of the immune and inflammatory responses.
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ABSTRACT: Toll-like receptor 5 (TLR-5), which is expressed on macrophages and dendritic cells (DCs), is a crucial cell surface molecule that senses microbial-associated molecular patterns and initiates host innate immune responses upon infection with invaders that express flagellin. Little information is known about the induction factors and mechanisms of TLR-5 expression. In this study, we demonstrate that all-trans retinoic acid (ATRA) significantly up-regulated TLR-5 expression in human macrophage THP-1 cells by co-activating NF-κB and the RARα receptor and inducing the differentiation of CD11b(-)CD11c(-) THP-1 cells to CD11b(+)CD11c(low) cells. Furthermore, when stimulated with flagellin, ATRA-induced THP-1 cells expressed multiple cytokines, including TNF-α, IL-1beta, and IL-12p40, and several co-stimulatory molecules, such as CD40, CD80, CD86, and MHC class I and II. We also showed that when ATRA-induced THP-1 cells were stimulated with flagellin, the cells displayed an allostimulatory capacity rather than phagocytic activity. Taken together, our findings suggest that ATRA is a crucial immunostimulatory cofactor that induces the activation of macrophages and their subsequent differentiation into dendritic-like cells.Immunology letters 04/2011; 136(1):97-107. DOI:10.1016/j.imlet.2011.01.001 · 2.37 Impact Factor
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ABSTRACT: Neuropathological processes in the central nervous system are commonly accompanied by an activation of microglia and astrocytes. The involvement of both cell populations in the onset and progress of neurological disorders has been widely documented, implicating both beneficial and detrimental influences on the neural tissue. Nevertheless, little is known about the interplay of these glial cell populations, especially under diseased conditions. To examine the effects of activated microglia on astrocytes purified rat astroglial cell cultures were treated with medium conditioned by purified quiescent (MCM[-]) or lipopolysaccharide (LPS)-activated rat microglia (MCM[+]) and subjected to a comparative proteome analysis based on two-dimensional gel electrophoresis. No significant down regulation of proteins was observed. The majority of the 19 proteins identified by means of nano HPLC/ESI-MS/MS in the 12 most prominent protein spots significantly overexpressed (> or =2-fold) in MCM[+] treated astrocytes are involved in inflammatory processes and oxidative stress response: superoxide dismutases (Sod), peroxiredoxins, glutathione S-transferases (Gst), nucleoside diphosphate kinase B, argininosuccinate synthase (Ass), and cellular retinol-binding protein I (Rbp1). Sod2, Rbp1, Gstp1, and Ass were also significantly increased on the mRNA level determined by quantitative RT-PCR. The upregulation of antioxidative enzymes in astrocytes was accompanied by a higher resistance to oxidative stress induced by H2O2. These results show that activated microglia change the expression of antioxidative proteins in astrocytes and protect them against oxidative stress, which might be an effective way to increase the neuroprotective potential of astrocytes under pathological conditions associated with oxidative stress and inflammation.Glia 08/2008; 56(10):1114-26. DOI:10.1002/glia.20683 · 6.03 Impact Factor
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ABSTRACT: Steroid hormones, calcitriol and retinoid acid are known to modulate inflammatory processes by influencing the synthesis and secretion of various cytokines. The aim of this thesis was to investigate the influence of the above mentioned hormones on the basal, as well as LPS-stimulated secretion of the pro-inflammatory cytokines TNF-alpha and IL-6. Mononuclear cells of male and female donors served as a model-system. Treatment with the synthetic glucocorticoid dexamethasone showed the expected reduction of cytokine secretion, confirming the validity of the method and of the model-system. Interestingly, the reducing effect was more pronounced in cells of male than in cells of female donors, respectively. Testosterone and estradiol treatment showed no effect on cytokine secretion. Calcitriol had different effects on cytokine secretion, meaning activating, reducing or no effect, presumably depending on the method-design and the sex of the cell donor. Interestingly, retinoic acid reduced TNF-a and IL-6 secretion regardless of LPS stimulation. Another focus of this work was to analyse the molecular signal transduction processes leading to reduced TNF-alpha secretion upon retinoic acid treatment. Reduced TNF-alpha transcript levels were observed, while TNF-alpha mRNA stability was not affected, indicating that retinoic acid presumably affects upstream intracellular pathways and transcription. Since MAP kinases are important in the process of LPS-stimulated cytokine transcription, especially in monocytic cells, I investigated the influence of retinoic acid on MAP kinase activity. While p38 MAP kinase activity was not affected, retinoic acid reduced the activity of ERK after 30 minutes of treatment, although no reduction of ERK activity could be observed after long-term treatment. The fast effect indicates that not de novo protein synthesis but a direct effect on ERK is involved in the retinoic acid mediated inhibition of TNF-alpha secretion.