I'm glad you found it useful! I was worried that it might be too dry for many people... but then, my readers do seem to have a longer attention span than the average person ;-).
(2 of 2) It is commonly stated that "vitamin D" regulates the immune system. This, or "calcitriol regulates the immune system" is not true. 25-hydroxyvitamin D > calcitriol intracrine and paracrine signaling plays a vital role in the ability of many, probably most, types of immune cells to respond to their changing circumstances. When this works well, the immune system, via the collective actions of all its cells, regulates itself.
In your point 3 you refer to the enzyme which hydroxylates 25-hydroxyvitamin D and calcitriol (vitamin D3 too?) on the 24th carbon, which is irreversible, with that compound being degraded and its components removed from the body. The 2007 article you cite was written before much was known about 25-hydroxyvitamin D > calcitriol intracrine and paracrine signaling, so the diagram only concerns the one hormonal function of calcitriol.
Thanks for the links to research on teeth. The actions you describe are from calcitriol produced by intracrine or paracrine signaling, not the very low, and generally stable, level of circulating calcitriol which functions as a hormone.
The trouble with the vitamin D research literature is that very few researchers properly understand 25-hydroxyvitamin D > calcitriol intracrine and paracrine signaling. This is because it has only recently been discovered, because there are no tutorials explaining these in the peer-reviewed literature, and because they were only known in detail in two cell types until 2021 with Chauss et al.
The effects of calcitriol you list in immune cells in "Immunomodulation - getting the balance right", "Anticancer activities", "Cardiometabolic effects" and "Neurological effects" and are not from the very low, generally stable, level of circulating calcitriol. This calcitriol is produced within the cells (intracrine signalling) or nearby cells (paracrine signaling) when the cell detects a particular, cell-type-specific, condition: "Cells in the human brain not only express the VDR but also produce the enzyme that synthesises calcitriol from circulating 25-hydroxyvitamin D."
Without lots of UV-B exposure of ideally white skin, or proper vitamin D3 supplementation, most people have only a fraction of the 50 ng/mL 125 nmol/L circulating 25-hydroxyvitamin D numerous cell types need to properly run their 25-hydroxyvitamin D > calcitriol intracrine and paracrine signaling systems. So a great deal of illness, neurodevelopmental problems etc. would cease to occur if everyone had at least 50 ng/mL.
Generally the kidneys can produce all the calcitriol they need with 20 ng/mL 50 nmol/L, which is what governments and many doctors think is sufficient for full health. Some doctors think 50 ng/mL 125 nmol/L is too much.
MS and many other inflammatory auto immune diseases can be suppressed with much higher levels of 25-hydroxyvitamin D (under medical supervision) or, in the absence of proper 25-hydroxyvitamin D levels, by (re)introducing helminths (intestinal worms): https://vitamindstopscovid.info/06-adv/.
I don't think I had seen the blood pressure vs. latitude graphs. They are from an extensive article by Matthias Wacker and the world's foremost vitamin D researcher, Michael Holick, which for some reason I had not seen before: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897598/.
For simplicity I suggest 50 ng/mL 125 nmol/L or more. The Quraishi graph shows the immune responses against bacterial infections falling off the further the level is below 50 ng/mL: https://vitamindstopscovid.info/00-evi/#00-50ngmL.
Prof Sunil Wimalawansa has recommendations for how much vitamin D3 to supplement, on average per day, to attain this, without the need for blood tests or medical monitoring. The amount depends on body weight and obesity status: https://vitamindstopscovid.info/00-evi/#00-how-much.
Since the UV-B which hydroxylates 7-dehydrocholesterol to vitamin D3 cannot be obtained naturally all year round (except in equatorial regions if there is no monsoon), since it damages DNA and so raises the risk of skin cancer and since vitamin D3 supplementation is safe, easy and inexpensive, I don't think there is any dilemma regarding how to attain the 50 ng/mL or more circulating 25-hydroxyvitamin D we need to be healthy: supplementation as Prof. Wimalawansa suggests.
It is not natural, but who cares? The natural way of UV-B light breaking a carbon ring is the only way Nature - and industry https://sci-hub.se/10.1016/B978-0-12-381978-9.10006-X - has of making vitamin D3 cholecalciferol.
I am 68. In hunter gather days I would probably have died some years ago. I intend to be bouncing around 30 years from now. That's not natural either. I am 67 kg and supplement somewhat more than Prof. W recommends: around 0.2 mg 8000 IU a day, with vitamin K2 and K1 and other nutrients. I didn't bother testing my 25-hydroxyvitamin D since I was confident it was well above 50 ng/mL and nowhere near 150 ng/mL (375 nmol/L), beyond which there is some risk of toxicity. (It is very hard to get to 150 ng/mL due to the increasing actions of the 24 hydroxylase enzyme.
My level earlier this year was 96 ng/mL or so, 240 nmol/L. This is unnatural - I think it would be almost impossible to attain it with UV-B skin exposure alone. It is enough to give many doctors conniptions. However, I am glad my level is hell-n-gone from the 20 ng/mL and less of many people all around the world, with such unhealthy, and very common, levels contributing greatly to the risk of dementia, which is close to ending the life of a friend who is a few years younger than me: https://vitamindstopscovid.info/00-evi/#3.3.
(1 of 2) Further to my comments on the first article, and the research cited at: https://vitamindstopscovid.info/00-evi/, it is a common mistake to regard all three compounds as "vitamin D" or "vitamin D3", when this term only applies properly to the first one: cholecalciferol. Rheinhold Veith pointed this out in 2004: "Why 'Vitamin D' is not a hormone, and not a synonym for 1,25-dihydroxy-vitamin D, its analogs or deltanoids" https://sci-hub.se/10.1016/j.jsbmb.2004.03.037. The vitamin D research literature would be much more informed and easier to understand if everyone had followed his suggestion.
Neither cholecalciferol nor the second compound, 25-hydroxyvitamin D (calcifediol AKA calcidiol) are signaling molecules. They do not act as hormones (endocrine, long-distance signaling via a compound in the bloodstream and cerebrospinal fluid). Nor do they act as intracrine or paracrine agents.
The third compound, 1,25-dihydroxyvitamin D calcitriol has one hormonal function, when a very low concentration (AKA level) of it, ca. 0.05 ng/mL, in the bloodstreams is produced and maintained by the kidneys as part of a larger system involving the parathyroid gland and osteocytes, which regulates calcium-phosphate-bone metabolism, as you describe in detail.
Calcitriol is a signaling molecule. While vitamin D3's (cholecalciferol's) role is primarily to be hydroxylated into 25-hydroxyvitamin D (primarily in the liver, but to some locally and systemically significant degree in other cells) and 25-hydroxyvitamin D's role is solely to be hydroxylated to become calcitriol, neither vitamin D3 cholecalciferol nor 25-hydroxyvitamin D are signaling molecules since they do not bind strongly to the "vitamin D receptor" molecule. This is best thought of the calcitriol receptor, since calcitriol binds strongly to it. The bound complex finds its way to the nucleus, binds to the retinol X molecule and the triple complex alters gene transcription > protein synthesis > cell behaviour, by increasing and decreasing the transcription of dozens to hundreds of genes, with each cell type where this occurs having its own set of up- and down-regulated genes.
Intracrine signaling involves a molecule produced in the cell, under particular circumstances - so the presence of the molecule conveys information about the cell's circumstances - with that molecule being the ligand (a small molecule which binds to a bigger molecule) of a receptor molecule in the cell's cytosol. It is a common mistake - as I made initially - to refer to this as "autocrine" signaling, which is similar. In autocrine signaling, the ligand leaves the cell and binds to receptors of the same cell which are bound to the cell's plasma membrane with their binding domain on the outside.
When calcitriol acts as in intracrine agent, it is not acting as a hormone. Paracrine signaling is like intracrine, or autocrine, signaling, but the ligand - in this case calcitriol - diffuses from the cell in which it was produced to raise the local (millimetres?) level of calcitriol which is sensed by nearby cells and changes their behaviour. In order for this to work, the local level needs to be raised well above the normal hormonal background level, which is very low.
As far as I know, calcitriol never acts as an autocrine agent. Chauss et al.'s 2021 "Autocrine vitamin D signaling switches off pro-inflammatory programs of Th1 cells" https://www.nature.com/articles/s41590-021-01080-3 is a brilliant elucidation of 25-hydroxyvitamin D > calcitriol intracrine signaling in Th1 regulatory lymphocytes. This significantly extends our knowledge of this process beyond the work done ten to twenty years ago by Martin Hewison and colleagues on 25-hydroxyvitamin D > calcitriol intracrine signaling in macrophages and dendritic cells. The work of these researchers is of monumental importance in human health. They should be honoured with the Nobel Prize.
The crucial thing to remember is that intracrine and paracrine signaling is not a continuous process. These are signaling systems - they convey information from one place to another. The conversion of 25-hydroxyvitamin D to calcitriol only occurs when the cell detects particular circumstances in that cell. Both the 1-hydroxylase enzyme and the VDR are produced (or produced in much greater levels) when the particular, cell-type-specific, condition is detected. Chauss et al. is dense an hard to read. I have a summary of the preprint: https://aminotheory.com/cv19/icu/#2020-McGregor-summary.
You wrote "regulate the activity of the cell that produced it". A better description would be "change" or "alter", the cell's behavior in important ways, in different ways for each cell type, in response to a cell-type-specific condition being detected by that cell.
Many types of immune cell use 25-hydroxyvitamin D > calcitriol intracrine signaling, and some use paracrine as well. We only know in detail how this works in macrophages, dendritic cells (Hewison et al.) and Th1 lymphocytes (Chauss et al.). Immune cells do not use hormonal signaling.
Any info of best form of vitamin D?
Coming soon!
That was a very informative great post. Thank you!
I'm glad you found it useful! I was worried that it might be too dry for many people... but then, my readers do seem to have a longer attention span than the average person ;-).
(2 of 2) It is commonly stated that "vitamin D" regulates the immune system. This, or "calcitriol regulates the immune system" is not true. 25-hydroxyvitamin D > calcitriol intracrine and paracrine signaling plays a vital role in the ability of many, probably most, types of immune cells to respond to their changing circumstances. When this works well, the immune system, via the collective actions of all its cells, regulates itself.
In your point 3 you refer to the enzyme which hydroxylates 25-hydroxyvitamin D and calcitriol (vitamin D3 too?) on the 24th carbon, which is irreversible, with that compound being degraded and its components removed from the body. The 2007 article you cite was written before much was known about 25-hydroxyvitamin D > calcitriol intracrine and paracrine signaling, so the diagram only concerns the one hormonal function of calcitriol.
I recall reading that the activity of the 24-hydroxylase enzyme is controlled (increased) not just by calcitriol levels (in which cells? just hormonal calcitriol or from intracrine / paracrine signaling?) but also by the local level of 25-hydroxyvitamin D. I have not read about the exact mechanisms, and I am not sure they are fully understood. Hormonal calcitriol levels only rise marginally with increasing circulating 25-hydroxyvitamin D: Fig 1 b of Tang et al. 2016 https://www.nature.com/articles/s41598-019-43462-6. Yet we can see by how the increase of 25-hydroxyvitamin D level with vitamin D3 intake rolls off at high levels: https://vitamindstopscovid.info/00-evi/Heaney-2015-GRH-distribution-11-.png from https://www.mdpi.com/2072-6643/7/3/1688 and https://vitamindstopscovid.info/00-evi/Vitamin-D-levels-Ekwaru-800x792.png from https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111265. So the 24-hydroxylation enzyme activity is progressively stronger the higher the circulating 25-hydroxyvitamin D level.
Thanks for the links to research on teeth. The actions you describe are from calcitriol produced by intracrine or paracrine signaling, not the very low, and generally stable, level of circulating calcitriol which functions as a hormone.
The trouble with the vitamin D research literature is that very few researchers properly understand 25-hydroxyvitamin D > calcitriol intracrine and paracrine signaling. This is because it has only recently been discovered, because there are no tutorials explaining these in the peer-reviewed literature, and because they were only known in detail in two cell types until 2021 with Chauss et al.
The effects of calcitriol you list in immune cells in "Immunomodulation - getting the balance right", "Anticancer activities", "Cardiometabolic effects" and "Neurological effects" and are not from the very low, generally stable, level of circulating calcitriol. This calcitriol is produced within the cells (intracrine signalling) or nearby cells (paracrine signaling) when the cell detects a particular, cell-type-specific, condition: "Cells in the human brain not only express the VDR but also produce the enzyme that synthesises calcitriol from circulating 25-hydroxyvitamin D."
Without lots of UV-B exposure of ideally white skin, or proper vitamin D3 supplementation, most people have only a fraction of the 50 ng/mL 125 nmol/L circulating 25-hydroxyvitamin D numerous cell types need to properly run their 25-hydroxyvitamin D > calcitriol intracrine and paracrine signaling systems. So a great deal of illness, neurodevelopmental problems etc. would cease to occur if everyone had at least 50 ng/mL.
Generally the kidneys can produce all the calcitriol they need with 20 ng/mL 50 nmol/L, which is what governments and many doctors think is sufficient for full health. Some doctors think 50 ng/mL 125 nmol/L is too much.
MS and many other inflammatory auto immune diseases can be suppressed with much higher levels of 25-hydroxyvitamin D (under medical supervision) or, in the absence of proper 25-hydroxyvitamin D levels, by (re)introducing helminths (intestinal worms): https://vitamindstopscovid.info/06-adv/.
I don't think I had seen the blood pressure vs. latitude graphs. They are from an extensive article by Matthias Wacker and the world's foremost vitamin D researcher, Michael Holick, which for some reason I had not seen before: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897598/.
Regarding the desired level of 25-hydroxyvitamin D: In 2008 the most prominent researchers called for 40 to 60 ng/mL (100 to 150 nmol/L) to be the target for general health: https://www.grassrootshealth.net/project/our-scientists/. In 2024 this campaign is being renewed, for the same levels: https://www.grassrootshealth.net/scientists-call-daction-public-health-2024/.
For simplicity I suggest 50 ng/mL 125 nmol/L or more. The Quraishi graph shows the immune responses against bacterial infections falling off the further the level is below 50 ng/mL: https://vitamindstopscovid.info/00-evi/#00-50ngmL.
Prof Sunil Wimalawansa has recommendations for how much vitamin D3 to supplement, on average per day, to attain this, without the need for blood tests or medical monitoring. The amount depends on body weight and obesity status: https://vitamindstopscovid.info/00-evi/#00-how-much.
Since the UV-B which hydroxylates 7-dehydrocholesterol to vitamin D3 cannot be obtained naturally all year round (except in equatorial regions if there is no monsoon), since it damages DNA and so raises the risk of skin cancer and since vitamin D3 supplementation is safe, easy and inexpensive, I don't think there is any dilemma regarding how to attain the 50 ng/mL or more circulating 25-hydroxyvitamin D we need to be healthy: supplementation as Prof. Wimalawansa suggests.
It is not natural, but who cares? The natural way of UV-B light breaking a carbon ring is the only way Nature - and industry https://sci-hub.se/10.1016/B978-0-12-381978-9.10006-X - has of making vitamin D3 cholecalciferol.
I am 68. In hunter gather days I would probably have died some years ago. I intend to be bouncing around 30 years from now. That's not natural either. I am 67 kg and supplement somewhat more than Prof. W recommends: around 0.2 mg 8000 IU a day, with vitamin K2 and K1 and other nutrients. I didn't bother testing my 25-hydroxyvitamin D since I was confident it was well above 50 ng/mL and nowhere near 150 ng/mL (375 nmol/L), beyond which there is some risk of toxicity. (It is very hard to get to 150 ng/mL due to the increasing actions of the 24 hydroxylase enzyme.
My level earlier this year was 96 ng/mL or so, 240 nmol/L. This is unnatural - I think it would be almost impossible to attain it with UV-B skin exposure alone. It is enough to give many doctors conniptions. However, I am glad my level is hell-n-gone from the 20 ng/mL and less of many people all around the world, with such unhealthy, and very common, levels contributing greatly to the risk of dementia, which is close to ending the life of a friend who is a few years younger than me: https://vitamindstopscovid.info/00-evi/#3.3.
(1 of 2) Further to my comments on the first article, and the research cited at: https://vitamindstopscovid.info/00-evi/, it is a common mistake to regard all three compounds as "vitamin D" or "vitamin D3", when this term only applies properly to the first one: cholecalciferol. Rheinhold Veith pointed this out in 2004: "Why 'Vitamin D' is not a hormone, and not a synonym for 1,25-dihydroxy-vitamin D, its analogs or deltanoids" https://sci-hub.se/10.1016/j.jsbmb.2004.03.037. The vitamin D research literature would be much more informed and easier to understand if everyone had followed his suggestion.
Neither cholecalciferol nor the second compound, 25-hydroxyvitamin D (calcifediol AKA calcidiol) are signaling molecules. They do not act as hormones (endocrine, long-distance signaling via a compound in the bloodstream and cerebrospinal fluid). Nor do they act as intracrine or paracrine agents.
The third compound, 1,25-dihydroxyvitamin D calcitriol has one hormonal function, when a very low concentration (AKA level) of it, ca. 0.05 ng/mL, in the bloodstreams is produced and maintained by the kidneys as part of a larger system involving the parathyroid gland and osteocytes, which regulates calcium-phosphate-bone metabolism, as you describe in detail.
Calcitriol is a signaling molecule. While vitamin D3's (cholecalciferol's) role is primarily to be hydroxylated into 25-hydroxyvitamin D (primarily in the liver, but to some locally and systemically significant degree in other cells) and 25-hydroxyvitamin D's role is solely to be hydroxylated to become calcitriol, neither vitamin D3 cholecalciferol nor 25-hydroxyvitamin D are signaling molecules since they do not bind strongly to the "vitamin D receptor" molecule. This is best thought of the calcitriol receptor, since calcitriol binds strongly to it. The bound complex finds its way to the nucleus, binds to the retinol X molecule and the triple complex alters gene transcription > protein synthesis > cell behaviour, by increasing and decreasing the transcription of dozens to hundreds of genes, with each cell type where this occurs having its own set of up- and down-regulated genes.
Intracrine signaling involves a molecule produced in the cell, under particular circumstances - so the presence of the molecule conveys information about the cell's circumstances - with that molecule being the ligand (a small molecule which binds to a bigger molecule) of a receptor molecule in the cell's cytosol. It is a common mistake - as I made initially - to refer to this as "autocrine" signaling, which is similar. In autocrine signaling, the ligand leaves the cell and binds to receptors of the same cell which are bound to the cell's plasma membrane with their binding domain on the outside.
When calcitriol acts as in intracrine agent, it is not acting as a hormone. Paracrine signaling is like intracrine, or autocrine, signaling, but the ligand - in this case calcitriol - diffuses from the cell in which it was produced to raise the local (millimetres?) level of calcitriol which is sensed by nearby cells and changes their behaviour. In order for this to work, the local level needs to be raised well above the normal hormonal background level, which is very low.
As far as I know, calcitriol never acts as an autocrine agent. Chauss et al.'s 2021 "Autocrine vitamin D signaling switches off pro-inflammatory programs of Th1 cells" https://www.nature.com/articles/s41590-021-01080-3 is a brilliant elucidation of 25-hydroxyvitamin D > calcitriol intracrine signaling in Th1 regulatory lymphocytes. This significantly extends our knowledge of this process beyond the work done ten to twenty years ago by Martin Hewison and colleagues on 25-hydroxyvitamin D > calcitriol intracrine signaling in macrophages and dendritic cells. The work of these researchers is of monumental importance in human health. They should be honoured with the Nobel Prize.
The crucial thing to remember is that intracrine and paracrine signaling is not a continuous process. These are signaling systems - they convey information from one place to another. The conversion of 25-hydroxyvitamin D to calcitriol only occurs when the cell detects particular circumstances in that cell. Both the 1-hydroxylase enzyme and the VDR are produced (or produced in much greater levels) when the particular, cell-type-specific, condition is detected. Chauss et al. is dense an hard to read. I have a summary of the preprint: https://aminotheory.com/cv19/icu/#2020-McGregor-summary.
You wrote "regulate the activity of the cell that produced it". A better description would be "change" or "alter", the cell's behavior in important ways, in different ways for each cell type, in response to a cell-type-specific condition being detected by that cell.
Many types of immune cell use 25-hydroxyvitamin D > calcitriol intracrine signaling, and some use paracrine as well. We only know in detail how this works in macrophages, dendritic cells (Hewison et al.) and Th1 lymphocytes (Chauss et al.). Immune cells do not use hormonal signaling.