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.
"Thus, complement is unlikely to account for the enhanced induction of TLR4-mediated IL-10 by cord blood plasma. Other plasma factors capable of enhancing TLR4-mediated IL-10 production include low-density lipoproteins , retinoic acid , and adenosine . The relative contribution of these and other factors to induction of TLR4-mediated IL-10 by whole plasma will require further investigations. "
[Show abstract][Hide abstract] ABSTRACT: Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection.
PLoS ONE 03/2012; 7(3):e33419. DOI:10.1371/journal.pone.0033419 · 3.23 Impact Factor
"It was demonstrated that the topical retinoids have significant anti–inflammatory effects in experimental trials . While ATRA downregulated the proinflammatory cytokines, the production of immune modulating cytokines was enhanced by ATRA . ATRA induced a "priming" of the immune system by increasing the number of T lymphocytes and LPS binding protein expression , and stimulated T cell proliferation by modulating IL–2–mediated signaling . "
[Show abstract][Hide abstract] ABSTRACT: Adoptive T cell therapy depends on the harvesting of the cells from the host, their activation in vitro, and their infusion back to the same host. The way of activating the T cells in vitro is a critical factor for their homing, survival and function in vivo. Sustaining T cell homing molecules, particularly CD62L, is benefic for the trafficking of the adoptive transferred cells.
The aim of the present study is to test whether insulin-like growth factor-1 (IGF-1), thymosin- α1 (T-α1) as well as all-trans retinoid acid (ATRA) alone or in combination with IL-2, IL-12, IL-15 can enhance the activation and survival phenotypes of antigen-activated T cells in vitro.
To this end, OT-1 transgenic T cells were used as a model. These CD8+ T cells recognize OVA peptide presented by MHC class-I. The results showed that antigen stimulation of OT1 cells resulted in their activation as evidenced by the decrease in surface expression of CD62L, analyzed for 3 days after antigen stimulation and was more pronounced on day 5. The addition of IL-12 or IGF-1 alone but not of IL-2, IL-15 augmented OT-1 cell activation measured on day 5. Interestingly, the combination of IL-12 with IGF-1 sustained the expression of CD62L on OT1 cells. Although the addition of ATRA alone or in combination with IL-12 resulted in decreases in CD62L expression on day 3, they showed a dose-dependent effect on the restoration of CD62L expression on day 5. The analysis of the activation-induced cell death (apoptosis) of OT1 cells showed an increased rate of death on day 5 than on day 3-post antigen stimulation. The addition of only IL-12 or IGF-1 alone, but not of IL-2, IL-15 or T- α1, decreased OT1 cell apoptosis on day 3. These anti-apoptotic effects of IL-12 and IGF- 1, however, were recovered on day 5-post stimulation.
In conclusion, these results indicate that the activation phenotype and the survival of antigen-specific T cells can be differently modulated by immunomodulatory factors, where, interleukin-12 and IGF-1 induced the favorable effect. These results have a significant implication for T cell adoptive immunotherapy in different settings.
Journal of medicine and life 11/2011; 4(4):399-406.
"TNF-␣ is an early pro-inflammatory cytokine that plays an important role in mechanisms of host defense against various microbial pathogens . Wang et al.  showed that ATRA enhances IL-10 production and inhibits IL-12 and TNF-␣ production in LPS-stimulated THP-1 cells. On the other hand, Ciacci-Woolwine et al.  indicated that TNF-␣ is an important cytokine expressed in primary human monocytes when stimulated with flagellin. "
[Show abstract][Hide abstract] 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.
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