Some notes on vitamin A and fish oils

[Guest guest]

Dear All;

In the last newsletter:

http://www.pscpartners.org/NewsVol-2-4.pdf

I tried to explain my thoughts on vitamin A and fish oils in the

control of enzymes of bile transport and metabolism, and how they might

protect against cholestasis and bile acid toxicity during inflammation.

Specifically, the key nuclear receptor retinoid X receptor alpha (RXRa)

is activated by a vitamin a metabolite (9-cis retinoic acid) and/or

docosahexaenoic acid (DHA) [a component of fish oil]. Maintenance of

the activity of RXRa is essential for the activity of many other

nuclear receptors involved in bile acid detoxification, bile transport

vitamin D function, and lipid metabolism, including the pregnane X

receptor (PXR), the farnesoid X receptor (FXR), the vitamin D receptor

(VDR) and the peroxisome proliferator activated receptors (PPARs). This

all ties in with the idea that in ulcerative colitis there appears to

be a loss of detoxification systems in the gut, and if this extended

over to the liver, it might result in cholestasis and hence bile duct

injury.

I've been reading up about T cells over the last 6 months, and I hope

to write about some new, exciting findings on T cells and IBD and other

autoimmune/autoinflammatory diseases in the next newsletter [sorry, I

have been really delayed in completing this next newsletter!].

Interestingly, key metabolities which also play a key role in

regulating T cells include vitamin A and fish oils.

In brief, the new discoveries in T cells include the discovery of a new

set of T helper cells called Th17 cells that produce interleukin-17,

which is a highly pro-inflammatory cytokine. This new class of T helper

cells has recently been implicated in animal models of rheumatoid

arthritis, multiple sclerosis and IBD. It turns out that the production

of these cells is stimulated by prostaglandin E2 [a pro-inflammatory

molecule derived from arachidonic acid]:

J Immunol. 2007 Jun 15;178(12):8138-47.

The Proinflammatory Effect of Prostaglandin E2 in Experimental

Inflammatory Bowel Disease Is Mediated through the IL-23->IL-17 Axis.

Sheibanie AF, Yen JH, Khayrullina T, Emig F, Zhang M, Tuma R, Ganea D.

Department of Physiology, Temple University School of Medicine,

Philadelphia, PA 19140.

Although Crohn's disease has been traditionally considered to be Th1-

mediated, the newly identified Th17 cells emerged recently as crucial

participants. Th1/Th17 differentiation is controlled primarily by the

IL-12 family of cytokines secreted by activated dendritic cells (DCs)

and macrophages. IL-23 and IL-12/IL-27 have opposite effects,

supporting the Th17 and Th1 phenotypes, respectively. We found that PGE

(2), a major lipid mediator released in inflammatory conditions, shifts

the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high

levels of PGE(2) exacerbate the inflammatory process in inflammatory

bowel disease through the IL-23-->IL-17 axis. We assessed the effects

of PGE(2) on IL-12, IL-27, and IL-23 and found that PGE(2) promotes IL-

23, inhibits IL-12 and IL-27 expression and release from stimulated

DCs, and subsequently induces IL-17 production in activated T cells.

The effects of PGE(2) are mediated through the EP2/EP4 receptors on

DCs. In vivo, we assessed the effects of PGE analogs in an experimental

model for inflammatory bowel disease and found that the exacerbation of

clinical symptoms and histopathology correlated with an increase in IL-

23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric

lymph nodes, and a substantial increase in the number of infiltrating

neutrophils and of CD4(+)IL-17(+) T cells in the colonic tissue. These

studies suggest that high levels of PGE(2) exacerbate the inflammatory

process through the preferential expression and release of DC-derived

IL-23 and the subsequent support of the autoreactive/inflammatory Th17

phenotype. PMID: 17548652.

It is well known that the eicosapentaenoic acid [EPA] in fish oils

competes with arachidonic acid, replacing it in membranes, and thus

reduces prostaglandin E2 production. This may offer an explanation for

the anti-inflammatory effects of fish oils.

The vitamin A metabolite, retinoic acid, has also recently been shown

to block the production of Th17 cells, and instead stimulate the

production of anti-inflammatory regulatory T cells (Tregs):

Science. 2007 Jun 14; [Epub ahead of print]

Reciprocal Th-17 and Regulatory T Cell Differentiation Mediated by

Retinoic Acid.

Mucida D, Park Y, Kim G, Turovskaya O, I, Kronenberg M, Cheroutre

H.

La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La

Jolla, CA 92037, USA.

The cytokine, transforming growth factor-beta (TGF-beta), converts

naïve T cells into regulatory T (Treg) cells that prevent autoimmunity.

However, in the presence of interleukin (IL)-6, TGF-beta has also been

found to promote differentiation of naïve T lymphocytes into pro-

inflammatory IL-17 cytokine-producing T helper 17 (Th-17) cells, which

promote autoimmunity and inflammation. This raises the question of how

TGF-beta can generate such distinct outcomes. Here we identified the

vitamin A metabolite, retinoic acid (RA), as a key regulator of TGF-

beta-dependent immune responses, capable of inhibiting the IL-6-driven

induction of pro-inflammatory Th-17 cells and promoting anti-

inflammatory Treg differentiation. These findings indicate that a

common metabolite can regulate the balance between pro- and anti-

inflammatory immunity. PMID: 17569825.

The bottom line is that vitamin A and fish oils (EPA and DHA) may play

key roles not only in detoxification of bile acids but also in

dampening the production of pro-inflammatory Th17 cells.

Other, novel ways of blocking Th17 cells are to inhibit interleukin-23

which seems to be a driver of Th17 cell production:

Gastroenterology. 2007 Jun;132(7):2359-2370.

Monoclonal Anti-Interleukin 23 Reverses Active Colitis in a T Cell-

Mediated Model in Mice.

Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB,

Kastelein RA

Department of Medicine, University of Alabama at Birmingham,

Birmingham, Alabama.

Background & Aims: Interleukin (IL)-23 supports a distinct lineage of T

cells producing IL-17 (Th17) that can mediate chronic inflammation.

This study was performed to define the role of IL-23 and Th17 cells in

chronic colitis in mice. Methods: Colitis was induced by transfer of a

cecal bacterial antigen-specific C3H/HeJBir (C3Bir) CD4(+) T-cell line

to C3H/HeSnJ SCID mice. Cytokines were measured by flow cytometry,

enzyme-linked immunosorbent assay, and real-time polymerase chain

reaction. Monoclonal anti-IL-23p19 was administered at the same time as

or 4 weeks after pathogenic CD4 T-cell transfer. A histopathology

colitis score was assessed in a blinded fashion. Results: The

pathogenic C3Bir CD4(+) T-cell line contained more cells producing IL-

17 than those producing interferon-gamma and these were distinct

subsets; after adoptive transfer to SCID recipients, Th17 cells were

predominant in the lamina propria of mice with colitis. Bacteria-

reactive CD4(+) Th1 and Th17 lines were generated. The Th17 cells

induced marked inflammation in a dose-dependent manner. Even at a dose

as low as 10(4) cells/mouse, Th17 cells induced more severe disease

than Th1 cells did at 10(6) cells/mouse. Monoclonal anti-IL-23p19

prevented and treated active colitis, with down-regulation of a broad

array of inflammatory cytokines and chemokines in the colon. Anti-IL-

23p19 induced apoptosis in colitogenic Th17 cells in vitro and in vivo.

Conclusions: Bacterial-reactive CD4(+) Th17 cells are potent effector

cells in chronic colitis. Inhibition of IL-23p19 was effective in both

prevention and treatment of active colitis. IL-23 is an attractive

therapeutic target for inflammatory bowel disease. PMID: 17570211.

It will be of future interest to see if antibodies against interleukin-

23 might prove to be as effective as antibodies against tumor necrosis

factor-alpha (TNF) [such as infliximab] in treatment of IBD.

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Sounds promising.

Thanks for keeping us up on this Dave.

Lee

[Guest guest]

Von,

I saw Lorenzo's oil as a young kid when it

just came out and remember I liked it. I saw it again a few months ago after

someone mentioned it this forum. It is amazing. I loved every minute of it. This

is the kind of movie that we need about transplants, not some kind of soap

opera like Heartland. Another movie that struck me like Lorenzo's oil was

" children of a lesser G.d " . That movie was a breakthrough for the

deaf community.

Chaim Boermeester, Israel

From: [mailto: ] On Behalf Of jumputah

Sent: Wednesday, June 20, 2007

04:34

To:

Subject: Re: Some

notes on vitamin A and fish oils

,

I always like your analysis. Understanding things at the receptor

and immunological level leads to more effective treatments.

Your efforts to understand PSC remind me a bit of the father in the

movie Lorenzo's Oil. It is a movie about a father who trys to

understand his son's rare incurable neurologic disease. Thanks for the

effort to understand and to communicate the essence to the rest of us.

Von