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Posts Tagged ‘IBD: Immunomodulatory Effect of Retinoic Acid – IL-23/IL-17A axis correlates with the Nitric Oxide Pathway’


IBD: Immunomodulatory Effect of Retinoic Acid – IL-23/IL-17A axis correlates with the Nitric Oxide Pathway

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/23472658

The Voice of Dr. Larry:

The correlation is significantly higher in patients with active CD. (which I would expect)

The all-trans retinoic acid piece for downregulation is quite interesting.  My work for all these years with Yves Ingenbleek on TTR also has an important relationship to AtRA.  

The transthyretin travels in the circulation as a 4 molecules of TTR carrying TH with one molecule of RBP carrying one molecule retinol.  There is a nuclear binding site for synthesis of retinoic acid and vitamin D released into the circulation, and a retinoic acid binding site when the retinol is released to the cell binding site.

When there is an acute inflammatory reaction, there is a concordant decrease of hepatic synthesis of TTR and of RBP, and other proteins, such as albumin, with the preferential increase of cytokines that are seen in the cytokine storm.   If the inflammatory reaction persists, then the effect is consequential.  The decrease in TTR is associated with a decrease in the bound RBP, which is lost in the urine, leading to a decreased transport of retinoic acid.  If this persists, there is a persistent catabolic state with breakdown of lean body mass. This is very much like an accelerated protein energy malnutrition state.  The breakdown of LBM is linearly related to TTR in plasma.  There is also an effect on S-adenosyl methionine, and a reactive increase in the homocysteine.  In long term veganism – there is elevated risk of AMI (the S/N ratio in vegetables is half that in meat.  The largest example of this is in septicemia.

In the paper attached, retinoic acid suppresses the effect of IL17, IL23 and IL6.  This is an anti-inflammatory role because of the relationship of liver suppression of TTR, RBP and so called negative-APPs.  Whether the retinoic acid would restore hepatic synthetic activity and an anabolic state is the question.

On Mon, Jan 25, 2016 at 5:48 PM, Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu> wrote:

J Interferon Cytokine Res. 2013 Jul;33(7):355-68. doi: 10.1089/jir.2012.0063. Epub 2013 Mar 8.

IL-23/IL-17A axis correlates with the nitric oxide pathway in inflammatory bowel disease: immunomodulatory effect of retinoic acid.

Rafa H1Saoula HBelkhelfa MMedjeber OSoufli IToumi Rde Launoit YMoralès ONakmouche M,Delhem NTouil-Boukoffa C.

Author information

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn’s disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.

PMID: 23472658

[PubMed – indexed for MEDLINE]

 

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/23472658

 

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