The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 80

93. How is adrenal insufficiency related to mast cell disease?

Adrenal insufficiency is when the adrenal glands do not make enough cortisol, a stress hormone your body needs to help your body respond to the things happening inside and around it. Not having enough cortisol is dangerous and can be fatal.

Adrenal insufficiency is not the same as adrenal fatigue. Patients with adrenal insufficiency demonstrate lower than normal levels of cortisol. Adrenal fatigue is a term that is used to describe a similar constellation of symptoms as seen in adrenal insufficiency but without the lower than normal serum cortisol level when tested. Adrenal fatigue is not well accepted in main stream medicine.

There are several steps involved in making cortisol. These steps use hormones to tell the body to make other hormones until cortisol is finally made. The molecules that are involved in getting the body to make cortisol are collectively called the HPA axis.

Mast cells interact with the HPA axis a lot and in several ways. I have written extensively about this before.

The activity of the HPA axis can either activate mast cells or stabilize them. It can tell the body to make epinephrine, which decreases mast cell activation. But it can also tell mast cells to make inflammation.

It also works in the other direction. Mast cell activation can activate the HPA axis or not, but it usually activates it. If mast cells generate enough inflammation, that can turn on the HPA axis, which in turn activates mast cells even more. This basically means that if you have frequent mast cell activation, your body can end up in a constant fight or flight response. The inflammation generated can be enormous.

When the body has been in a stress response for too long, the adrenal glands can stop making cortisol, causing adrenal insufficiency. This can cause mast cell activation.

Steroids like prednisone mimic the action of cortisol, the stress hormone. Steroids are sometimes used to treat mast cell disease. The purpose of the steroids is to make cells like mast cells stop causing inflammation. If you take systemic steroids like prednisone routinely, your body can become confused and stop making cortisol on its own. This means that when you stop taking the prescription, your body will not have enough cortisol, causing adrenal insufficiency. This activates mast cells in a huge way. Patients often have a hard time getting back to a good baseline without steroids if they have been on steroids for a while.

There is an autoimmune disease called Addison’s Disease that causes adrenal insufficiency. MCAS sometimes occurs secondary to Addison’s.

 

For further reading, please visit the following posts:

The effects of cortisol on mast cells: Cortisol and HPA axis (Part 1 of 3)
The effects of cortisol on mast cells: Cortisol and HPA axis (Part 2 of 3)
The effects of cortisol on mast cells: Cortisol and HPA axis (Part 3 of 3)
Corticotropin releasing hormone, cortisol and mast cells
Mood disorders and inflammation: High cortisol and low serotonin

The effects of cortisol on mast cells: Part 3 of 3

In some cases, glucocorticoids can immediately treat issues with immune activation. This immediate action is not well understood.  In animal models, glucocorticoids can stop allergic reactions in five minutes and significantly decrease short term histamine release. Mostly though, glucocorticoids mitigate mast cell activation through delayed actions. This is one of the reasons why premedication with steroids prior to surgery or procedures is recommended to start the day before.

Glucocorticoids affect gene expression, which is one of the reasons they take time to work. Gene expression is very complicated and is highly regulated by cells. Genes are part of your DNA. Think of each gene as a message.  When your cell wants to make something using a gene, like a protein, it makes a copy of the message in the gene and then takes it to another part of the cell to make the protein. There are many molecules that affect how easy it is to make something from a gene.  Some molecules make it easier and others make it harder.  Transcription factors are molecules that sit by genes that make it easier for their message to be made. Interfering with making the message and getting it to the part of the cell where it can make something, like the protein, can drastically alter the behavior of a cell.

One of the major ways that glucocorticoids interfere with making the message is with glucocorticoid receptors. Many people know that receptors are often on the outside of a cell and they are activated when a molecule fits into the receptor like a key into a lock.  Glucocorticoid receptors do not work like that.  They are small molecules inside cells that are changed when glucocorticoids bind to them.

Cortisol, or other glucocorticoids, bind to the glucocorticoid receptors inside mast cells. When this happens, they interfere with the transcription factors so it is really hard to use the genes. Some of these transcription factors are called NF-kB and AP-1.  When glucocorticoid receptors have been activated in the mast cell, the transcription factors can’t help to use the genes.

Cytokines are molecules that cells use to “talk” to each other. Another kind of signal.  Glucocorticoids directly interfere with use of cytokine genes so that they aren’t made.  Mast cells make many cytokines and they are responsible for a lot of late phase allergic symptoms.  Manufacture of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, GM-CSF, TNF and IFN-g (interferon gamma) can all be suppressed with glucocorticoids.

If the cytokine genes have already been used, glucocorticoids can still prevent them from being made. When you use a gene to make something, it creates a messenger RNA (mRNA) that carries the message.  If the mRNA falls apart, nothing will be made from the gene. Glucocorticoids make the messages fall apart before making anything for many cytokines, including IL-1, IL-2, IL-6, IL-8, TNF and GM-CSF.

References:

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Molecular and Cellular Endocrinology 2013: 380, 119-126.

Varghese R, et al. Association among stress, hypocortisolism, systemic inflammation and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016: 116, 344-348.

Zappia CD, et al. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Scientific Reports 2015: 5.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011: 335(1), 2-13.

Sinniah A, et al. The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil. International Immunopharmacology 2016: 32, 87-95.

The effects of cortisol on mast cells: Part 2 of 3

Glucocorticoids, like cortisol, can affect mast cells in many ways. As I discussed in my previous post, there are many ways for mast cells to release mediators when activated. In all of these pathways, there are many molecules involved that carry the signal, like people passing the Olympic torch. In mast cells, one of the molecules that suppresses inflammatory activation signal is called SLAP (yes, really).  Cortisol increases the amount of SLAP in mast cells so inflammatory activation signals are suppressed.

An important step in degranulation is changing the amount of calcium inside the cell and moving it to different parts of the cell. In some studies, glucocorticoids can affect this movement of calcium. Other studies have found that in some pathways, glucocorticoids don’t affect calcium movement, but instead interfere with things like the IgE receptor.

Cortisol is also thought to directly inhibit stem cell factor (SCF) binding to the CKIT receptor. When SCF binds to the CKIT receptor, this sends a signal to the mast cell to stay live.  This means that taking glucocorticoids can let mast cells die at the appropriate time. SCF also tells mast cells to go to inflamed spaces.  By blocking this signal, glucocorticoids suppress inflammation.

One of the ways that molecules carry a signal is by changing the next molecule in the pathway. A big way that cells changing molecules is by chopping off a piece of them called a phosphate group.  This is done by special enzymes called phosphatases.  Glucocorticoids affect the availability of phosphatases so they aren’t able to get to the right part of the cell to carry the signal.  When this happens, there is less activation and less histamine release.

Arachidonic acid is the molecule modified to make eicosanoids (leukotrienes, thromboxanes and prostaglandins.) Glucocorticoids directly interfere with the production of these molecules in multiple ways.  The first way is by interfering with COX-2, one of the enzymes that makes prostaglandins.  Another way is by preventing arachidonic acid from being released to a place where they can be turned into leukotrienes, thromboxanes and prostaglandins.  This occurs because glucocorticoids increase the amount of a powerful anti-inflammatory molecule called annexin-I.  Annexin-I inhibits the molecule that releases the arachidonic acid, called phospholipase A2.

Annexin-I was the subject of an important paper earlier this year. In trying to identify exactly how mast cell stabilizers like ketotifen and cromolyn work, the researchers discovered that treatment with mast cell stabilizers decreased degranulation and increased annexin-I made by mast cells.  They also found that glucocorticoids had the same effect.

References:

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Molecular and Cellular Endocrinology 2013: 380, 119-126.

Varghese R, et al. Association among stress, hypocortisolism, systemic inflammation and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016: 116, 344-348.

Zappia CD, et al. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Scientific Reports 2015: 5.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011: 335(1), 2-13.

Sinniah A, et al. The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil. International Immunopharmacology 2016: 32, 87-95.

The effects of cortisol on mast cells: Cortisol and HPA axis (Part 1 of 3)

Things I’m not great at: Knowing how many posts I need to cover all the effects cortisol has on mast cells.  So this is the first of three posts on cortisol and mast cells.  Then we will get back to the tables breaking down the effects of hormones on mast cells.
Cortisol is a glucocorticoid steroid hormone with far reaching anti-inflammatory actions. It is the product of a very complex endocrine system called the HPA axis.  HPA stands for hypothalamus-pituitary-adrenal.  The hypothalamus is in the brain and the pituitary is a small structure on the edge of the hypothalamus.  The adrenal glands are above the kidneys.

The hypothalamus, pituitary and adrenal glands all release a number of hormones that affect many bodily functions. Briefly, the hypothalamus receives signals from the nervous system to make corticotropin releasing hormone (CRH).  CRH induces the pituitary to make adrenocorticotropin hormone (ACTH). ACTH induces the adrenal glands to make cortisol.

Cortisol is most well known as the stress hormone, although it has many other functions. It can be released as a response to inflammation or physical or emotional trauma.  In such instances, signals from the nervous system tell the hypothalamus that it needs to make CRH.  CRH triggers vasodilation and increased vascular permeability to allow immune cells move from the bloodstream to inflamed spaces in tissue.  CRH also triggers manufacture of ACTH, which then triggers manufacture of cortisol.

When cortisol levels are high in the adrenal gland, epinephrine can be made from norepinephrine. Cortisol is thought to regulate the enzyme that makes epinephrine at several steps in the process.  Epinephrine is also part of the stress response and participates in the fight-or-flight response.

The role for which glucocorticoids are most often prescribed is suppression of inflammation. Cortisol production is initiated very early in an inflammatory response. Cortisol counteracts vasodilation seen by many inflammatory mediators.  Cortisol also decreases vascular permeability so immune cells are not able to easily leave the bloodstream and move into tissues.  Cortisol also affects gene expression so that inflammatory products are not made as much and anti-inflammatory products are made more.  (This will be discussed in great detail when I cover how cortisol affects mast cells.)

A number of synthetic glucocorticoids, like prednisone and dexamethasone, have similar behaviors and functions. The medication hydrocortisone functions the most like cortisol in the body.  Synthetic glucocorticoids stay in the blood longer and are more bioavailable than cortisol.  The amount of cortisol produced by the body changes throughout the day in time with other functions.  Synthetic glucocorticoids cannot mimic these changes exactly and are thus inferior to cortisol.  Small changes in amount of glucocorticoid can have major effects.

References:

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Molecular and Cellular Endocrinology 2013: 380, 119-126.

Varghese R, et al. Association among stress, hypocortisolism, systemic inflammation and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016: 116, 344-348.

Zappia CD, et al. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Scientific Reports 2015: 5.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011: 335(1), 2-13.