Modulation of T Cell and Innate Immune Responses by Retinoic Acid

Raverdeau, Mathilde; Mills, Kingston H. G.

doi:10.4049/jimmunol.1303245

Cited by 187 publications

(171 citation statements)

References 93 publications

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“…To further prove the concept that ERK1/2 can be activated even in the absence of MEK1 and this is signal dependent, we tested the effect of retinoic acid (RA) on Mek1 d/d Sox2 Cre BMDMs. RA is a biologically active metabolite of vitamin A and evidence suggests that RA can negatively regulate Th1 type cytokines and favors production of Th2 type cytokines in APCs and T cells [44, 45]. Thus, we investigated whether the presence of RA can negatively regulate IL-12 production in MEK1 deficient BMDMs in response to LPS and similarly lead to ERK activation.…”

Section: Resultsmentioning

confidence: 99%

MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 production in bone marrow derived macrophages

Bouhamdan

Bauerfeld

Talreja

et al. 2015

Cellular Signalling

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The mitogen activated protein kinases ERK1/2 play an important role in response to toll like receptor (TLR) activation and cytokine production, including IL-10 and IL-12. Here, we examined the role of MEK1 in ERK1/2 activation in response to TLR4 agonist by using bone marrow-derived macrophages (BMDMs) from wild type (WT) and Mek1d/dSox2Cre mice. Our data demonstrates that MEK1 is essential for ERK1/2 activation in response to LPS. Furthermore, stimulation of the TLR4 receptor of BMDMs derived from Mek1d/d Sox2Cre mice showed enhanced STAT4 phosphorylation and increased IL-12 secretion, but exhibited a significantly lower IL-10 production as compared to WT macrophages. Most interestingly, TLR ligation in the presence of recombinant IL-10 (rIL-10) or retinoic acid (RA) led to ERK1/2 activation independent of MEK1 in BMDMs derived from Mek1d/dSox2Cre mice and led to inhibition of STAT4 and decreased IL-12 levels. Collectively, these data suggest that MEK1 is required for TLR4 mediated ERK activation and in turn regulates production of IL-10 and IL-12. It also indicates that ERK1/2 can be activated independent of MEK1 in the presence of IL-10 and RA and this activation negatively regulates IL-12, but positively regulates IL-10 production. These findings may have significant implications for the development of drugs that modulate MEK1 activity in the treatment of inflammatory, autoimmune and proliferative diseases such as cancer.

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Section: Resultsmentioning

confidence: 99%

MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 production in bone marrow derived macrophages

Bouhamdan

Bauerfeld

Talreja

et al. 2015

Cellular Signalling

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“…Retinoic acid is a highly regulated signaling molecule that is involved in a host of dermatological, immunological and neurological functions through binding to the retinoic acid receptors and retinoid X receptors 12,13,[78][79][80][81][82] . As such, the metabolic pathways that are involved in the regulation of retinoic acid represent potential targets that can be exploited to alter concentrations of retinoic acid in vivo.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases

Foti

Diaz

Douguet

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The CYP26s are responsible for metabolizing retinoic acid and play an important role in maintaining homeostatic levels of retinoic acid. Given the ability of CYP2C8 to metabolize retinoic acid, we evaluated the potential for CYP2C8 inhibitors to also inhibit CYP26. In vitro assays were used to evaluate the inhibition potencies of CYP2C8 inhibitors against CYP26A1 and CYP26B1. Using tazarotenic acid as a substrate for CYP26, IC 50 values for 17 inhibitors of CYP2C8 were determined for CYP26A1 and CYP26B1, ranging from $20 nM to 100 mM, with a positive correlation observed between IC 50 s for CYP2C8 and CYP26A1. An evaluation of IC 50 's versus in vivo C max values suggests that inhibitors such as clotrimazole or fluconazole may interact with CYP26 at clinically relevant concentrations and may alter levels of retinoic acid. These findings provide insight into drug interactions resulting in elevated retinoic acid concentrations and expand upon the pharmacophore of CYP26 inhibition.

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“…This research was an experimental laboratory research with The Post Test-Only Control Group Design using experimental animals as objects of research [16]. The number of samples was determined by the Federer's formula for experimental research, using 24 mice which were divided into four groups.…”

Section: Methodsmentioning

confidence: 99%

Vitamin A modulation toward IL-12, IFN-γ production and macrophage activity in malaria disease

Iswari¹,

Susanti²,

Dafip³

2016

AIP Conference Proceedings

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Modulation of T Cell and Innate Immune Responses by Retinoic Acid

Cited by 187 publications

References 93 publications

MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 production in bone marrow derived macrophages

MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 production in bone marrow derived macrophages

Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases

Vitamin A modulation toward IL-12, IFN-γ production and macrophage activity in malaria disease

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