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1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis.

Muthian G, Raikwar HP, Rajasingh J, Bright JJ.
Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Vitamin D deficiency is commonly observed in MS patients and vitamin D supplements reduce the clinical symptoms of EAE and MS. Earlier studies have shown that in vivo treatment with vitamin D analogs ameliorates EAE in association with the inhibition of IL-12 production and Th1 differentiation. The mechanisms in the regulation of Th1 response by vitamin D in EAE/MS are, however, not known. We show that in vivo treatment of C57BL/6 and SJL/J mice (i.p.) with 100 ng of 1,25 dihydroxyvitamin D3, on every other day from Day 0-30, ameliorates EAE in association with the inhibition of IL-12 production and neural antigen-specific Th1 response. In vitro treatment with 1,25(OH)2D3 inhibited IFNgamma-induced tyrosine phosphorylation of STAT1, without affecting JAK2, in EOC-20 microglial cells. Treatment of activated T cells with 1,25(OH)2D3 also inhibited the IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 in association with a decrease in T cell proliferation in vitro. These findings highlight the fact that vitamin D modulates JAK-STAT signaling pathway in IL-12/IFNgamma axis leading to Th1 differentiation and further suggest its use in the treatment of MS and other Th1 cell-mediated autoimmune diseases. Copyright 2006 Wiley-Liss, Inc.

PMID: 16547967 [PubMed - indexed for MEDLINE]
Journal of Neuroscience Research May 06

http://www.ncbi.nlm.nih.gov/entrez/quer ... s=16547967

IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis.

Spach KM, Nashold FE, Dittel BN, Hayes CE.
Department of Nutritional Sciences, College of Agricultural and Life Sciences, University of Wisconsin, 433 Babcock Drive, Madison, WI 53706, USA.

Multiple sclerosis (MS) results from an aberrant, neuroantigen-specific, T cell-mediated autoimmune response. Because MS prevalence and severity decrease sharply with increasing sunlight exposure, and sunlight supports vitamin D(3) synthesis, we proposed that vitamin D(3) and 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) may protect against MS. In support of this hypothesis, 1,25-(OH)(2)D(3) strongly inhibited experimental autoimmune encephalomyelitis (EAE). This inhibition required lymphocytes other than the encephalitogenic T cells. In this study, we tested the hypothesis that 1,25-(OH)(2)D(3) might inhibit EAE through the action of IL-10-producing regulatory lymphocytes. We report that vitamin D(3) and 1,25-(OH)(2)D(3) strongly inhibited myelin oligodendrocyte peptide (MOG(35-55))-induced EAE in C57BL/6 mice, but completely failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene. Thus, a functional IL-10-IL-10R pathway was essential for 1,25-(OH)(2)D(3) to inhibit EAE. The 1,25-(OH)(2)D(3) also failed to inhibit EAE in reciprocal, mixed bone marrow chimeras constructed by transferring IL-10-deficient bone marrow into irradiated wild-type mice and vice versa. Thus, 1,25-(OH)(2)D(3) may be enhancing an anti-inflammatory loop involving hemopoietic cell-produced IL-10 acting on brain parenchymal cells and vice versa. If this interpretation is correct, and humans have a similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and neuro-protective functions of sunlight and vitamin D(3). In this way, a genetic IL-10-IL-10R pathway defect could interact with an environmental risk factor, vitamin D(3) insufficiency, to increase MS risk and severity.

PMID: 17056528 [PubMed - indexed for MEDLINE]

Journal of Immunology November 06

http://www.ncbi.nlm.nih.gov/entrez/quer ... &DB=pubmed

Not sure Vit D belongs in "Natural Approach" anymore

Since reading so much research, I have increased my D3 to 4,000 a day since I almost never go outside during the week.

Right now I am waiting for another snowstorm, so I may end up staying in the house all weekend too.

gwa

How much Vit D is considered toxic? I've read that you should be careful about taking too much. I am hardly ever in the sun and even though my diet includes Vit D, I'm sure it's not enough. My multivitamin has 400 IUs. I'm not sure how much more I should be taking. Any suggestions?

there is recent research posted by nick that says 10,000IU is fine. earlier stuff i read said that skin can come up with that much (white skin i presume) in half an hour of full bod exposure (that sounds like a fun study). there is other research that says 4,000IU is what you need to maintain your levels over the winter, probably need less in the summer. there is research to show that a 400IU supplement does not keep you level when you don't have natural exposure, it takes you down over time. also, if you're low already then you want to take really big doses so it doesn't take you months to get into the optimal range. i took 50,000 IU per day for 10 days and had no ill effects. since then i took 4000IU per day til i went to australia, and i've been naughty since i got back just taking maybe 800IU per day but i've got to get back on the program for sure. you can get your blood tested to help you decide if you need to do a short term megadose. the research has gone from saying you need a serum level of 50 to prevent rickets, to saying you need 75 or 80 to prevent osteoporosis, to saying you need over 100 (i target 150) for immune health. they say the lower incidence of MS in japan, although it is a northern latitude country, may be due to their high dietary consumption of D3 in fish. (i think it also has to do with them differentialing out a lot more cases of vitamin B12 deficiency there than they do here since their normal range starts alot higher than ours).

My experience with the Japanese health care system was that they told patients very little about their problems or diagnosis. To think that the Japanese doctors would take the time to do blood tests for vitamin deficiency and relate it to the patient would surprise me very much.

I do think that the typical Japanese fish diet, which is normally consumed three times a day, may well add enough omega 3 and vit
D to their diet to keep them healthier than the typical western diet.

Also, Japanese eat a lot of salmon, especially salted or smoked salmon.

I would not have taken such a high dose of Vit d had I not been going to a yearly appointment with my PCP in the next month. I am not convinced that the 4000 units is safe just because it is posted on the internet. I can have my blood checked next month to make sure I am not getting too much of it.

Since I stay indoors so much and get very little sun (I am as white as a sheet) my D levels are probably low even though I do eat wild Pacific salmon at least twice a week.

gwa

hey there i don't think 4000 is just "posted on the internet", that's backed up in research... i took 50,000 per day for 10 days and i went from 72 to 149 and like i said, no ill effects.

i don't have personal experience with japanese health care, but i do know that the main differential diagnosis for MS is b12 deficiency, and neuros are supposed to look for that before going any further with the idea of MS. whether they tell their patients what they're doing or not is another thing.

ps. you probably should take calcium and magnesium with the vitamin D.

I do take calcium and magnesium with Vit D. I would like to see some of the top name research universities give their take on the suggested minimum amounts of Vitamin D3. If you have more info from the likes of Harvard, Yale or John Hopkins, please post it.

Most of what I have seen from researchers is that more research is needed to determine the low and high recommended levels of this vitamin. I started taking more recently because of recent research discussing connections to low intake of vit D and cancers.

It is obviously a needed vitamin, but I do not feel comfortable that anyone knows the correct amount to take daily.

gwa

Thanks for the responses. I have to have my 3 month blood test with my GP this month so maybe I'll ask her to test me and then ask her opinion too. I have my yearly appt. with my neuro in March but he's not very helpful when it comes to supplements.

Please post what your GP says. The last time I went to mine, she told me to take 800 units of D3 daily and 1200 of calcium.

gwa

here's one but it's only from creighton and boston universities, probably doesn't measure up.
http://www.ajcn.org/cgi/content/abstract/77/1/204

i suppose my personal experience isn't worth anything either but we'll see what scoob's gp says, that's probably better info.

Here is a link to some suggestions by a Harvard nutritionist regarding D3. The main jist is that they recommend that a person take no more than 2000 IU daily unless directed otherwise by a physician.

You can get figures all over the place, but for me, I do not believe that definite knowledge currently exists for determining the best amount to take.

Too much D3 is harmful too, so a person has to figure in all the sources from where we get this vitamin and supplement accordingly until better criteria is determined.


http://www.hsph.harvard.edu/nutritionso ... aminD.html




Should people consider taking vitamin D supplements? If so, who might benefit most from supplements?


Because we may need more vitamin D than most people get in typical diets, and because of the potential downsides
of excessive sun exposure, supplementation may be warranted. It may turn out that most people may benefit
from supplements.

The elderly, dark-skinned individuals, obese individuals, and those who avoid the sun are at risk for vitamin D
deficiency or less-than-adequate intakes. People who live in more northern latitudes (such as Boston, Mass.,
Milwaukee, Wis., or Portland, Ore. ) can only make vitamin D from March through September; supplies stored from
summer sun exposure must last for many months, and by late winter, most of these individuals may be deficient.

Although definitive evidence is not available currently, supplements of at least 1,000 IU per day of vitamin D
may be warranted. I suggest not taking more than 2,000 IU per day of vitamin D in supplement form without
specific medical reasons until more definitive data are available concerning the benefits and risks. Look for
supplements that contain vitamin D3 (cholecalciferol), rather than vitamin D2 (ergocalciferol), since vitamin D3 is three to four times more potent than vitamin D2. As always, it is important to discuss use of supplements with
your personal health care provider.

The aim of the Harvard School of Public Health Nutrition Source is to provide timely information on diet and nutrition for clinicians, allied health professionals, and the public. The contents of this Web site are not intended to offer personal medical advice, which should be obtained from a health-care provider. The information does not mention brand names, nor does it endorse any particular products.

©2006 President and Fellows of Harvard College.

HARVARD SCHOOL OF PUBLIC HEALTH

I'm with jimmylegs in thinking

i suppose my personal experience isn't worth anything either

.

But here is my situation: I added D3 about 6 months ago. I have not had a blood test for D lately; I should schedule one this spring. In the meantime, I'll just say that I'm SURE that 4000IU per day won't hurt you! In fact, the previous unexplained bruising that I had ALL the time has stopped since I began supplementation! There may be no connection, but human nature makes me think that there MIGHT be.

Reading has informed me that normal insulin secretion is dependent on Vitamin D and, since hyperinsulinemia is my "angle," that is the reason for my taking it. However, I have seen no change in my MS condition since starting. Nevertheless, I continue.

i'm done with this thread, good luck on 2000IU per day

Hey gang

There seems to be confusion here over how much D3 to take, how much is toxic ,ideal levels, timing, etc.

DIRECT-MS has a lot of material at our site which addresses these issues and furthermore all articles are referenced to peer reviewed medical journals. We also have material, both in text and in Webcast formats, from one of the world's foremost experts on vitamin D, Dr. Vieth.

DIRECT-MS is also financing two ongoing research initiatives. Overviews of both are found here.

In particular, the study entitled A Dose/Safety Study of Vitamin D for Persons with Multiple Sclerosis , once completed should quell any misconceptions about how much is too much. Keep in mind your friendly neighborhood GP or neurologist will most likely have a poor knowledge of vitamin D toxicity.

A nice start for your knowledge base of MS and vitamin D can be read here.

Cheers
Nick

PS I don't think taking a large hit of vitamin D will accelerate your serum concentration. I believe your body will stil need 1 to 2 months to convert any intake, be it from UVR exposure or supplements, to the therapeutic internal hormone.


DIRECT-MS material

Booklets

Direct-MS produces information booklets on various aspects of multiple sclerosis. These booklets are listed below and a PDF of each one can be opened and downloaded by clicking on the title.

Alternately we can mail you a hard copy of any of the booklets. Just write or email us and let us know which ones you would like sent to you. Don’t forget to include your mailing address. There is no charge for this service.

Booklet #1 Take Control of Multiple Sclerosis This booklet discusses the main causal factors of MS and, with this information as a guide, it lays out our recommendations for nutritional strategies to help control MS.

Booklet #2 Protect Your Family from Multiple Sclerosis
This booklet emphasizes the high risk for contracting MS of first-degree relatives of persons with MS. It discusses the causal factors of MS with special emphasis on vitamin D deficiency as a primary cause. Finally it demonstrates that adequate vitamin D can likely prevent MS in most cases and provides a recommended supplementation regime.

Booklet # 3 Multiple Sclerosis: The Alberta Disadvantage
This booklet demonstrates that the province of Alberta, the home of DIRECT-MS, has by far the highest rates of MS in the world: Prevalence 340/1000,000; Incidence 20/100,000.
Data and arguments are provided to support the argument that the main reason for the “MS Epidemic” is that all the main causal factors are present in Alberta, with low vitamin D supply being especially problematic.

Presentations

We have found that a Voiced PowerPoint presentation (‘Webcast’) is an effective way to communicate the science and the recommendations for nutritional strategies for controlling MS and preventing it in the first place.

The latest presentation is Prospects for Vitamin D Nutrition. The discussion is narrated by Dr Reinhold Vieth of the departments of Pathology and Laboratory Medicine, Mount Sinai Hospital and Laboratory Medicine and Pathobiology, University of Toronto.

Dr Vieth addresses the topics of:
Vitamin D and Human Evolution
Clinical relevance of higher vitamin D intakes
Toxicology of Vitamin D

The second webcast is entitled Preventing Multiple Sclerosis and is the second in a series of web casts regarding nutrition and Multiple Sclerosis. The focus of the Prevention presentation is how MS can be easily, safely and inexpensively prevented by focusing on protective factors. This is a must see for those people with MS who have children.

Our first webcast, Nutritional Strategies for Controlling Multiple Sclerosis, addresses similar issues. It presents the probable causes of MS and how to effectively control those elements. A review of the protective factors and how to incorporate them into your lifestyle is also covered.

Nick wrote:PS I don't think taking a large hit of vitamin D will accelerate your serum concentration. I believe your body will stil need 1 to 2 months to convert any intake, be it from UVR exposure or supplements, to the therapeutic internal hormone.

Ok, is that a "think"/"belief" or something from a study?