Retinoic Acid Enhances the Production of IL-10 While Reducing the Synthesis of IL-12 and TNF-α 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.

Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI

“…The kinetics of RA signaling is consistent with the transition of macrophage phenotypes after IR-AKI. 16,51 Our model is also consistent with data indicating that ATRA represses inflammatory cytokine production by cultured macrophages, [52][53][54][55] and PTECs secrete factors that induce expression of alternatively activated markers in cultured macrophages. [15][16][17] Our data indicate that RA signaling provides another layer of temporally and spatially controlled signaling that regulates dynamic changes macrophage phenotypes after AKI.…”

“…On this basis, we propose that inhibition of PTEC RA signaling decreases M2 spectrum macrophage markers, but at the same time a compensatory increase in local RA synthesis acts through a different mechanism to repress inflammatory renal macrophages after IR-AKI. Because in vitro studies indicate that RA has direct suppressive effects on inflammatory macrophages, [52][53][54][55] it is likely this is a direct effect of RA on renal macrophages ( Figure 10B). …”

Markers of Innate Immune Function Are Associated with Vitamin A Stores in Men

“…This proinflammatory:antiinflammatory ratio was examined because it is a useful way to represent the balance between such responses and because a previous study reported a marginally significant increase in this ratio as a result of vitamin A supplementation in a human intervention trial using data from whole blood cultures stimulated with a T-cell mitogen (phytohemaglutinin) (12). Whereas these previous data suggest that vitamin A supports production of TNFa, perhaps by supporting the Th1 response, in vitro studies show that retinoic acid suppresses LPS-induced TNFa production in murine macrophages (8,52,53) as well as cord blood mononuclear cells (54). In agreement with these findings, serum TNFa significantly increased after immunization in the low VA group but not in the high VA group, perhaps as a result of stimulation of innate immune cells via toll-like receptors by components of the livevirus YFV vaccine.…”

Retinoid ameliorates experimental autoimmune myositis, with modulation of Th cell differentiation and antibody production in vivo

“…Alternatively, Am80 could inhibit cytokine production directly. Retinoids have been shown to down-regulate TNF␣ expression on lipopolysaccharide-stimulated macrophages (38). In addition, retinoids down-regulated Toll-like receptor 2 and CD14 expression on monocytes and reduced expression of cytokines, such as TNF␣ and IL-6, Figure 6.…”