The sunlight vitamin and the cell's defense systems

Scientists today understand that vitamin D has many benefits that do not just add up to building new bones and that many people do not have enough of this type of vitamin. Does the common lack of vitamin D contribute to the development of serious diseases?

By Luz A. Tavara-Mendoza and John H. White

In the past it was called "sunlight healing", and at the beginning of the 20th century, before the age of antibiotics, it was the only effective treatment known for tuberculosis. No one knew why the treatment was beneficial, and all they knew was that tuberculosis patients sent to rest in sunny regions often returned healthy. The exact same "treatment" was already discovered in 1822 as an effective treatment for another historical calamity, rickets, a disfiguring childhood disease caused by the body's inability to produce hard bones. The rickets spread in the 18th and 19th centuries in Europe when the processes of industrialization and the transition from the villages to the air-polluted cities took place. At that time, a doctor in the city of Warsaw noticed that the problem was relatively rare among Polish village children. He began to conduct experiments on urban children, and found that it was possible to cure them of leprosy by exposing them to sunlight.

In 1824, German scientists discovered that fish oil was also very effective against rickets, but this treatment was not widely used, partly because doctors did not yet understand that food may contain tiny amounts of invisible nutrients important to health. Another hundred years passed until scientists linked nutritional treatments for rickets with the beneficial effects of sunlight. At the beginning of the 20th century, researchers tested rats that had induced rickets, and they found that feeding them pieces of skin exposed to the sun helped them heal, like fish oil. The decisive factor common to skin and fish oil was identified only in 1922 and was called vitamin D. At that time the idea of ​​"vital amines" - or vitamins - was a new and popular scientific topic. Follow-up studies that examined in depth the functions of the vitamin in the body were largely influenced by the opinion that vitamin D is one of the nutrients whose tiny amounts are essential for health and are available to humans only in food.

Due to the connection to rickets, for 50 years after the discovery of the molecule, most of the research on the subject was concerned with examining its role in building bones and understanding its activity in the kidneys, intestines and the skeleton itself as a means of controlling the entry of calcium from the bloodstream into the bones and its exit from them. However, in the last 25 years, the studies on the functions of vitamin D have expanded and discovered that the "sunshine vitamin" is essential for other things besides building bones. Extensive evidence now shows that the substance causes strong anti-cancer activity and serves as an important regulator of immune system responses. In addition to this, many of the recently discovered benefits of vitamin D are at their peak when the levels of the substance in the blood are significantly higher than the level found in many populations. These findings and epidemiological data linking low levels of vitamin D and diseases strengthen the argument that the widespread lack of vitamin D contributes to the development of some serious diseases.

Multipurpose switch

In order to understand the new findings, it is worth going back and reviewing what vitamin D actually is and how the human body uses it. People can get the molecule known as vitamin D from certain food sources such as fatty fish and fish oil, and today also from food supplements. However, we can also produce it ourselves through a chemical reaction that occurs in the skin when it is exposed to ultraviolet light in the B range (UVB). Therefore, it seems that vitamin D is not a vitamin at all, since moderate exposure to UVB avoids the need to obtain it through food. But in the temperate regions of the world for six months of the year there is not enough UVB light to stimulate the production of vitamin D in the skin, and in these months it is essential to obtain the substance from food sources.

The term vitamin D is actually a designation for two very similar molecules that come from each of the sources, light and food. Vitamin D3, also called cholecalciferol, is created in skin cells called keratinocytes from the substance 7-hydro-cholesterol, and is a chemical breakdown product of cholesterol in response to UVB light. Vitamin D2, also called ergocalciferol, is a derivative of a similar plant sterol, and it differs slightly from vitamin D3 in its structure. However, not one of these molecular versions participates in biological activity in the body. First, each of the molecules undergoes a series of changes using appropriate enzymes in a process called hydroxylation. The process adds two-thirds of a water molecule (OH group) to the vitamin molecule and produces the substance 25-hydroxy-vitamin D (or 25D).

The conversion occurs mainly in the liver, but some cell types in the skin are able to perform it locally as well. However, most of the vitamin D found in the bloodstream is 25D, which is made in the liver. When the body needs the vitamin, another and final conversion step is carried out in which another substance is produced, which is the biologically active substance: 25D molecules undergo another step of hydroxylation to obtain the substance 1,25-di-hydroxy-vitamin D (or 1,25D). The enzyme responsible for this task, 1-alpha-hydroxylase, was first discovered in the kidneys, and the processing process that occurs in the kidneys is responsible for most of the current supply of 1,25D in the body.

Scientists today understand that many other tissues, including the cells of the immune system and the skin, are capable of producing the enzyme and converting 25D themselves. The skin is therefore a unique tissue capable of producing the substance 1,25D by itself when exposed to UVB radiation. However, an important source of biologically active vitamin D whose importance was not properly appreciated until recently is the local production of 1,25D in other tissues through the conversion of 25D found in the bloodstream. When you consider the wide range of action of vitamin D, you understand why certain types of cells may need local production of its active form.

The 1,25D molecule functions as a switch capable of "turning on" and "turning off" genes in every tissue in the human body. This form of vitamin D binds to a protein called the vitamin D receptor, VDR, which serves as a transcription factor within the cell nucleus. When the VDR protein binds to 1,25D, it looks for its partner, the protein called retinoid-X receptor, RXR, and binds to it. The resulting conjugate binds to a specific region of the cellular DNA adjacent to the target gene. The binding of the proteins to the DNA activates a cellular machine that begins to copy the adjacent gene and produce a copy that the cell can translate into a protein.

The substance 1,25D causes the cell to produce a certain protein, and thus it actually changes the function of the cell. This ability to stimulate genetic activity in different cells is the basis for the broad physiological effect of vitamin D. Since vitamin D is produced in one tissue, moves throughout the body and affects many other tissues, it can technically be defined as a hormone. In fact, the VDR protein belongs to a family of proteins that act as receptors in the cell nucleus and respond to powerful steroid hormones such as estrogen and testosterone.

It is estimated that 1,25D regulates the activity of at least 1,000 genes, including some genes involved in the processing of calcium in the body, and this explains its well-known role in building bones. However, in the last 20 years, scientists have identified many other genes that are affected by the activity of vitamin D in the body, including genes that play key roles in a variety of cell defense mechanisms.

Vitamin D fortifications

Since the 80s, several lines of evidence have suggested that vitamin D helps the body defend against cancer. Many epidemiological studies have found a clear inverse relationship between sun exposure and the incidence of several types of cancer. Studies that examined animals and cell cultures supported this assumption and helped to identify the mechanisms involved.

For example, in mice used as a model for head and neck cancer, it was found that the compound EB1089, an artificial version of 1,25D, reduced tumor growth by 80%. Similar results were obtained in animals used as a model for breast cancer and prostate cancer. Identifying the genes activated by this artificial version of vitamin D helped explain the body's response to the compound. Cell division or uncontrolled growth are hallmarks of cancer cells. In the experiments it was found that the compound EB1089 changed the mode of action of several genes and thus suppressed the cells' ability to divide. One of the genes that the compound stimulates is the GADD45a gene, which is activated in normal cells after their DNA has been damaged. The gene triggers a reaction that stops their division and reduces the risk that the damaged healthy cells will turn into cancer cells. In addition, EB1089 activates genes that increase the differentiation of cancer cells and bring them to a more mature developmental stage that limits their ability to reproduce.

Another dozen or so genes involved in managing the cell's energy balance and removing toxins from it have been linked to the anti-cancer activity of EB1089. This experimental compound, designed to mimic the biological activity of 1,25D without the calcium in the blood and tissues reaching a toxic level, is one of several possible drugs for cancer treatment that pharmaceutical companies are developing based on the effective anti-cancer properties of vitamin D.

Indeed, our research group at McGill University was engaged in 2004 in studying the activity of vitamin D in relation to cancer. During the research we accidentally discovered a completely different form of physiological defense controlled by 1,25D. Many of the genes whose activity is controlled by vitamin D were discovered in recent years by scientists who scanned the human genome to find sections called vitamin D response sites (VDREs) - special DNA code sequences adjacent to the genes to which the VDR-RXR protein conjugate binds. In collaboration with Sylvie Mader from the University of Montreal, we scanned the entire genome using a computer algorithm to locate VDREs and to map their location compared to genes in their vicinity.

The mapping studies not only helped us better understand some of the anticancer actions of vitamin D, but also revealed VDREs located near two other genes encoding peptides with antimicrobial activity: cathelicidin and beta-defensin 2. These two small proteins act as natural antibiotics against a variety of Wide range of bacteria, viruses and fungi. This was the tip of the iceberg for further studies we conducted in human cell cultures. In these studies we found that exposure to 1,25D resulted in a relatively moderate increase in the production of the defensin beta 2 protein in the cells. However, in some other cell types, including immune system cells and keratinocytes, there was a sharp increase in cathelicidin production. We also showed that immune system cells that were treated with 1,25D and then exposed to disease-causing bacteria released substances, probably cathelicidin, that killed the bacteria.

Philip Liu and Robert Modlin of the University of California, Los Angeles and their collaborators greatly advanced this line of research in 2006. They showed that the cells of the human immune system respond to the cell wall of bacteria by producing VDR proteins and the enzyme that converts 25D into the biologically active 1,25D in the bloodstream. In the experiments conducted by this research group, these events stimulated the cells of the immune system to produce cathelicidin and perform antimicrobial activity against a variety of bacteria, including a bacterium that is perhaps the most fascinating of all: the tuberculosis bacterium, Mycobacterium tuberculosis. The group thus revealed for the first time a plausible mechanism underlying the effective and mysterious treatment of tuberculosis by sunlight. The sun baths stimulated the cells of the patients' immune system to produce the raw material needed to produce a natural antibiotic that fought the tuberculosis bacteria.

As the physiology of vitamin D becomes clearer, researchers realize that some of the substance's protective actions in the body probably derive from its functions in the source tissue of the molecule: the skin. Therefore, it is possible to understand the inhibition of the proliferation of cancer cells by 1,25D, since it is known that overexposure to UVB radiation is harmful to the DNA of skin cells, and may cause them to become cancerous. Some speculate that the antimicrobial response controlled by vitamin D evolved to compensate for the vitamin's role in suppressing some other immune system responses, particularly those that cause severe inflammation. Unfortunately, many of us have experienced "burnt" skin due to overexposure to UVB. At the tissue level, the redness comes from fluid accumulation and inflammation. Although controlled inflammation is a mechanism that helps heal wounds and helps the immune system fight infection, excessive inflammation can cause damage.

It is therefore not surprising that quite a few studies now show that 1,25D also acts as an anti-inflammatory agent through an effect on the reactions of the immune system. For example, different subtypes of immune cells communicate with each other through the secretion of substances called cytokines, which trigger certain immune responses. Vitamin D has been found to suppress an excessive immune response by blocking cytokine communication.

The first direct evidence for the natural role of vitamin D in preventing inflammation was found in experiments conducted in the early 90s in animals. The experiments showed that mice treated with 1,25D were protected from inflammation usually caused by wounds and the irritating chemical di-nitrobenzene. In contrast, mice that suffered from vitamin D deficiency showed hypersensitivity to the same injuries. The role of vitamin D as an immunosuppressant immediately brings to mind a new range of possibilities for the treatment of autoimmune diseases caused by excessive cytokine release, such as autoimmune diabetes, multiple sclerosis (MS) and irritable bowel disease, using vitamin D or its derivatives.

Over the years, scientists have realized that many types of cells, including cells of the immune system, are able to utilize 1,25D found in the blood circulation and convert 25D in the blood into the active form of the vitamin. This supported the proposition that the anti-inflammatory actions of 1,25D are not limited to sunburned skin cells.

Epidemic shortage?

The understanding that 1,25D has a wide range of biological activity, in addition to its role in calcium balance, is consistent with much epidemiological evidence that low levels of vitamin D are strongly associated with several types of diseases, including cancer, autoimmune diseases and even infectious diseases such as influenza, and seasonal changes in morbidity rates. In addition to this, both in the laboratory and in clinical studies it was found that many of the physiological reactions described earlier are particularly effective when the concentration of 25D in the body is higher than the level common in many populations. Among the members of the vitamin D research community, there is a broad consensus that the level of vitamin D in the bodies of many people in the temperate regions of the world is considerably lower than the concentration necessary to maintain health, especially in the winter months.

The penetration of UVB radiation through the Earth's atmosphere is more efficient in the tropical regions than in the temperate regions, where it reaches mainly in the summer. Most humans obtain vitamin D primarily through UVB exposure. The level of D25 in the population therefore decreases as the latitudes increase, however there are deviations from this trend resulting from ethnic and nutritional differences and changes in the local climate and altitude. According to the activity of vitamin D in the regulation of genetic activity, a clear connection was found between an increase in latitude and an increased risk of contracting certain diseases, especially autoimmune diseases such as multiple sclerosis.

Multiple sclerosis is a chronic disease that worsens over time, and is caused by an attack by the cells of the immune system on the myelin sheath, which surrounds the nerve fibers of the central nervous system and protects them. The incidence of the disease is considerably higher in the regions farthest from the equator in North America, Europe and Australia, and there is convincing evidence linking this distribution to too little exposure to UVB. The progress of the disease and the frequency of attacks indicate a cycle based on the seasons: the activity of the disease reaches its peak in the spring (after winter, when the D25 levels in the body are lowest) and it calms down in the fall after receiving a boost of vitamin D3 in the summer. Scientists at the University of Southern California found in 79 pairs of identical twins an inverse relationship between increased exposure to the sun in childhood and the risk of developing multiple sclerosis during life. The risk of the twins who spent more time outside the home in their childhood of getting MS decreased by up to 57%.

Similar risk patterns were also found for autoimmune diabetes, Crohn's disease, which is an autoimmune disease that affects the intestines, and several types of malignant diseases. For example, the incidence of bladder cancer, breast cancer, colon cancer, ovarian cancer and rectal cancer among the population of the northern United States is twice as high as the incidence among the population of the southern United States.

In addition to many studies that found a connection between exposure to the sun and the incidence of diseases, recently studies were conducted that found a similar correlation between the risk of getting multiple sclerosis and the concentration of 25D in the blood fluid, as measured by a direct blood test. Researchers at Harvard University's School of Public Health conducted a large-scale survey that examined stored blood fluid samples from about seven million US Army and Navy personnel and compared them to their medical records to find those who developed multiple sclerosis between 2004 and 1992. The researchers found that the risk of having the disease after the blood test was considerably lower among subjects whose 25D concentration in their blood fluid was high at the time of the test. The risk of soldiers whose 25D concentration in their blood fluid was higher than 40 ng/ml of contracting the disease was 62% lower than the risk of soldiers whose 25D concentration in their blood was lower than 25 ng/ml of contracting it.

Measuring the levels of 25D in the blood is the most accepted method for monitoring available vitamin D in the body. The accepted health standard, based mainly on the need to build bones, states that 25D concentrations in the range of 30-45 ng/ml are considered the minimum necessary. A concentration of 25D in the blood fluid below the range of 29-21 ng per ml is considered an insufficient concentration and is often accompanied by reduced bone density. Some symptoms of rickets may appear when the concentration drops below 20 ng/ml and then the risk of colon cancer also increases.

Unfortunately, such low concentrations are not that rare, especially in winter. In February and March 2005, for example, a study that surveyed 420 healthy women in Northern European countries, Denmark (Copenhagen, 55° latitude), Finland (Helsinki, 60°), Ireland (Cork, 52°) and Poland (Warsaw, 52°) found that 92% of adolescent girls in these countries suffered from 25D levels lower than 20 ng per ml, and of these 37% suffered from a severe deficiency of less than ten ng of 25D per ml. It was also found that 37% of the older women suffered from vitamin D deficiency and 17% of them suffered from a severe deficiency.

Besides latitude, there are other factors that contribute to a vitamin D deficiency, the most important of which is skin color. White skin produces vitamin D six times faster than dark skin, because the high level of melanin in dark skin blocks the penetration of UV radiation. Thus the 25D levels among African Americans in the United States are generally about half of the 25D levels among whites in the United States. In fact, data collected in the National Health and Nutrition Examination Survey in the United States show that 42% of African-American women tested had severe 25D deficiency, reaching concentrations of less than 15 ng per ml of blood fluid.

There is no doubt that the growing public awareness of the skin damage caused by prolonged exposure to the sun also contributes to the lack of vitamin D. Tanning creams filter radiation and reduce the production of vitamin D in the skin by more than 98%, if they are applied properly to the areas of the body exposed to the sun. However, in order to produce enough vitamin D to maintain normal health, one must be exposed to the sun to an extent that causes at least slight redness. To do this, most light- and medium-skinned people in North America need to be exposed to sunlight for 5 to 15 minutes between 10 a.m. and 3 p.m. during the summer.

Vitamin D supplements may solve the common deficiency in temperate regions, but there is controversy about the correct dose. The American Academy of Pediatrics recommends a daily intake of 200 international units (IU) for children, but many researchers believe that this is a lower value than is desirable even to prevent rickets. [One international unit of vitamin D is defined as the biological activity caused by the consumption of 25 ng of vitamin D2 or D3 - the editors.] The recommended daily intake for adults in North America and Europe is between 200 IU and 600 IU, according to age. In 2006, after reviewing many studies comparing vitamin D intake and the concentration of 25D formed from it in the blood fluid, researchers from the Harvard University School of Public Health and others concluded that the recommended daily intake is inadequate. They believe that at least half of adults in the United States need to consume at least 1,000 IU of vitamin D3 per day to raise 25D concentrations in their blood fluid to a healthy minimum of 30 ng/ml. There is no rule that allows to calculate the levels of 25D in the blood fluid produced as a result of taking supplements because of individual differences and possibly also due to the different deficiency rates. A study among pregnant women showed, for example, that daily doses of 6,400 IU raised the levels of 25D in the blood fluid a marked increase up to a concentration of about 40 ng/ml and then stabilized. It was also found that vitamin D2 is less effective than vitamin D3 in raising 25D concentrations in the blood fluid and maintaining them over time.

There is no doubt that toxic overdose of vitamin D supplements is possible, although this has only been observed after prolonged daily consumption of 40,000 IU or more. On the other hand, no toxicity of vitamin D has ever been observed that originates from prolonged exposure to the sun. For reference: an adult white woman exposed to the summer sun in a bikini produces about 10,000 IU of vitamin D in 15 to 20 minutes. Longer exposure to the sun does not lead to the creation of larger amounts of vitamin D, because UVB radiation also breaks down the vitamin and thus its accumulation in the skin is inhibited.

Accumulating evidence suggests that mild and long-term effects of vitamin D deficiency, and even a mild deficiency, may accumulate and manifest later in life in increased susceptibility to bone fractures, increased susceptibility to inflammation and autoimmune diseases, and higher rates of certain types of cancer. The study clearly implies that there is a need, at the very least, to increase awareness of the broad benefits of vitamin D, a well-founded medical consensus regarding the desired amount of sun exposure, and clear recommendations regarding the optimal daily dose of vitamin D from dietary sources. All these will bring great benefit to the general public.

key concepts

Vitamin D, which for many years was attributed only a role in bone formation, is active in practically all organs of the human body and has a strong effect on the reactions of the immune system and the defense mechanisms of cells.

The human body can get the vitamin from food or produce it in the skin exposed to the sun. However, blood tests show that many people have less vitamin D in their blood than is needed to keep them healthy.

A clear link between low levels of vitamin D and cancer, autoimmune diseases, and infectious diseases suggests that a change in daily intake recommendations for this essential nutrient is needed.

Basic facts

Production of an active vitamin

The term "vitamin D" is actually a name for two molecules that are slightly different from each other: molecule D3 that is produced in the human skin and molecule D2 that comes from plants and that humans can obtain from food. Both versions of vitamin D must go through several steps of chemical conversion by enzymes in order for their form to be the biologically active form, known as 1,25D.

Vitamin D sources

Vitamins D3 and D2 are found naturally in some foods and are even added to some "enriched" products. The food provides a relatively small amount of vitamin D compared to the vitamin D produced in the skin in response to UVB light (IU = international units).
Fish oil (one teaspoon): 1,360 IU of D3.
Cooked tuna, sardines, mackerel or salmon (100-85 g): 360 IU-200 IU of D3.
Fresh shiitake mushrooms (100 g): 100 IU of D2.
Dry shiitake mushrooms (100 g): 1,600 IU of D2.
Egg yolk: 20 IU of D3 or D2.
Fortified dairy products, orange juice or cereal (one serving): 100 IU–60 IU of D3 or D2.
Whole-body UVB exposure (for 15 to 20 minutes in the middle of the day in mid-summer, for fair-skinned people): 10,000 IU of D3.

Vitamin D in action

Wide activity garden switch

The biologically active form of vitamin D, called 1,25D, "turns on" certain genes and stimulates them to produce the proteins they code for. These proteins may have a local or widespread physiological effect in the body. The explanation is that 1,25D controls the activity of more than 1,000 different genes in at least a dozen tissues and cell types throughout the body.

About the authors

Luz A. Tavera-Mendoza (Tavera-Mendoza) and John H. White studied together the molecular activity of vitamin D in human cells in White's laboratory at McGill University. They uncovered aspects of the vitamin's role in cancer prevention and discovered, with their colleagues, that vitamin D regulates the action of genes involved in cell responses to microbial invaders. Tavara-Mendoza is currently a postdoctoral fellow at Harvard Medical School conducting research on vitamin D and breast cancer. After the two researchers learned first-hand in the laboratory about the health benefits of the vitamin, they began taking its supplements in the months when there is not enough sunlight in the northern cities where they live, in order to produce the necessary amount of the vitamin in the skin. White takes 4,000 international units of vitamin D3 every day during the "vitamin D winter" months. Tavara-Mendoza takes 1,000 international units.

How much 25D is needed?

The assessment of the amount of vitamin D available in the body is based on measuring the concentration of 25D in the blood fluid. A concentration of 45-30 ng per ml of blood fluid is considered the minimum concentration necessary for bone health, although there are beneficial cellular reactions that operate with maximum efficiency at higher concentrations. The health risks increase at concentrations lower than 30 ng per ml. Concentrations of more than 150 ng/ml cause the accumulation of excess calcium in the blood and tissues and may cause symptoms of toxicity.

Vitamin D: that's all the difference

Accumulating evidence suggests that chronically low levels of vitamin D increase the risk of several serious diseases.
Examples of findings based on vitamin D levels in the blood fluid in the population or on UV exposure:
Those suffering from 25D concentrations lower than 20 ng per ml of blood fluid have a 50-30% increased risk of developing breast cancer, prostate cancer and colon cancer.
Women living in high latitudes (eg, Norway and Iceland) have a five times higher risk of ovarian cancer than women at the equator.
Women aged 55 and older living in Nebraska who take 1,100 IU of D3 daily for three years have a 77% reduced risk of all cancers compared to their female counterparts living in Nebraska who do not take IU.
Those with D25 levels higher than 40 ng/ml of blood fluid have a 62% reduced risk of getting multiple sclerosis compared to those with levels lower than 25 ng/ml.
Finnish children who received a daily dose of 2,000 IU of vitamin D3 in their first year of life have an 80% reduced risk of developing autoimmune diabetes (type 1) throughout their lives.

A worldwide problem

"The Winter of Vitamin D"
Most people get vitamin D mainly through exposure to UVB radiation. The location and the season therefore affect the risk of a certain population to suffer from a vitamin deficiency. During periods of the year, known as the "vitamin D winter", UVB radiation in certain latitudes is too weak to even start the production of the vitamin in the skin. The ozone blocks UVB rays, therefore their intensity is at its peak near the equator, where the path of the sun's rays through the atmosphere is the shortest, and vitamin D production is possible all year round. A sharper penetration angle at higher latitudes weakens the strength of UVB rays to a level too low for vitamin production, especially in winter.

More on:

Unraveling the Enigma of Vitamin D. Beyond Discovery Series, National Academy of Sciences, 2003. www.beyonddiscovery
.org/content/view.
article.asp?a=414

1,25-Dihydroxyvitamin D3 Is a Direct Inducer of Antimicrobial Peptide Gene Expression. Tian-Tian Wang et al. in Journal of Immunology, Vol. 173, pages 2909–2912; 2004.

The Pleiotropic Actions of Vitamin D. Roberto Lin and John H. White in BioEssays, Vol. 26, no. 1, pages 21–28; January 2004.

The Urgent Need to Recommend an Intake of Vitamin D That Is Effective. Reinhold Vieth et al. in American Journal of Clinical Nutrition, Vol. 85, no. 3, pages 649–650; March 2007.

Vitamin D Deficiency. Michael F. Holick in New England Journal of Medicine, Vol. 357, no. 3, pages 266–281; July 19, 2007.