Interplay between mast cells and hormones: Part 3 of 8

Hormone Location released Major functions Interaction with mast cells Reference
Dopamine Hypothalamus

Adrenal gland (medulla)

Inhibit prolactin released from pituitary

Increase heart rate and blood pressure

Inhibit norepinephrine release

 

 

Enhances mast cell degranulation

Perpetuates immediate and late phase hypersensitivity reactions

H3 receptor activation inhibits dopamine production

Dopamine is released by mast cells

H1 inverse agonists increase dopamine release

Histamine increases dopamine release

Mori T, et al. D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells. Journal of Dermatological Science 2013: 71, 37-44.

Xue L, et al. The effects of D3R on TLR4 signaling involved in the regulation of METH-mediated mast cell activation. International Immunopharmacology 2016: 36. 187-198.

Endothelin Stomach Promotes smooth muscle contraction of stomach

Very potent vasoconstrictor

Activates mucosal mast cells

Mast cells regulate endothelin levels to prevent loss of blood flow to tissues

Boros M, et al. Endothelin-1 induces mucosal mast cell degranulation and tissue injury via ETA receptors. Clin Sci (Lond) 2007: 103(48), 31S-34S.

Hultner L, Ehrenreich H. Mast cells and endothelin-1: a life-saving biological liaison. Trends Immunol 2005: 26(5), 235-238.

 

Epinephrine/ adrenaline Adrenal gland (medulla), sympathetic nervous system Fight or flight response

Increases heart rate, force of heart contraction, blood pressure, energy breakdown, production of ACTH, bloodflow and energy to the brain and muscles

Suppresses nonessential functions and significantly decreases GI motility and excretion of urine and stool

Epinephrine inhibits IgE mediated released of histamine, prostaglandins and TNF

Epinephrine inhibits mast cell proliferation, adhesion and movement within the body SCF reduces action of epinephrine on mast cells by decreasing B2 adrenergic receptors

 

 

Cruse G, et al. Counterregulation of beta(2)-adrenoceptor function in human mast cells by stem cell factor. J Allergy Clin Immunol 2010: 125(1), 257-263.

Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: a review. Front Pharmacol 2015.

Erythropoietin Kidney Stimulate red blood cell production

Protects nerve cells and tissues

During low oxygen events, mast cells express receptors for erythropoietin

Erythropoietin can bind at the CKIT receptor

Decreases inflammatory response to infection (decreases IL-6 and TNF)

Wiedenmann T, et al. Erythropoietin acts as an anti-inflammatory signal on murine mast cells. Mol Immunol 2015: 65(1), 68-76.
Estradiol and other estrogens Ovaries, placenta, adipose tissue, testes Drive female secondary sex characteristics

Increase metabolism, uterine and endometrial growth, bone production, and the release of cholesterol in bile

Increase production of proteins in liver, cortisol, sex hormone binding globulin, somatostatin, clotting factors II, VII, IX, X, antithrombin III and plasminogen, HDL, triglycerides

Decrease LDL, production of adipose tissue, GI motility

 

 

Modulate salt and water retention

Inhibits programmed cell death of germ cells

E2 is a very potent mast cell degranulator

E2 drives mast cell degranulation in ovaries to trigger ovulation

Enhances IgE mediated degranulation

Increased production of leukotrienes

Increases mast cell density in ovaries

Zaitsu M, et al. Estradiol activates mast cells via a non-genomic estrogen receptor-a and calcium influx. Mol Immunol 2007: 44(8), 1977-1985.

Zierau O, et al. Role of female sex hormones, estradiol and progesterone, in mast cell behavior. Front Immunol 2012: 3, 169.

Follicle stimulating hormone (FSH) Pituitary Stimulates maturation of ovarian follicles

Stimulates maturation of seminiferous tubules, production of sperm and production of androgen binding protein

Triggers mast cell degranulation

Increases mast cell density in ovaries

Theoharides TC, Stewart JM. Genitourinary mast cells and survival. Transl Androl Urol 2015: 4(5), 579-586.

Jaiswal K, Krishna A. Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex of mice. Acta Physiol Hung 1996: 84(2), 183-190.

Gastric inhibitory polypeptide/ glucose-dependent insulinotropic polypeptide (GIP) Duodenum, jejunum Triggers release of insulin

Involved in fatty acid metabolism

Involved in bone formation

May suppress release of stomach acid triggered by histamine McIntosh CHS, et al. Chapter 15 Glucose-Dependent Insulinotropic Polypeptide (Gastric Inhibitory Polypeptide; GIP). Vitamins & Hormones 2009: 80, 409-471.
Gastrin Stomach, duodenum, pancreas Release of gastric acid

Release of pepsinogen, the precursor to pepsin

Triggers secretion of pancreatic enzyme

Triggers emptying of gallbladder

Increases stomach motility

Triggers release of histamine in enterochromaffin-like cells to trigger gastric acid secretion

Triggers mast cell degranulation

Gastrin releasing peptide, which induces gastrin release, triggers histaminergic itching response

Akiyama T, et al. Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. Pain 2014: 155, 80-92.

 

Histamine effects on neurotransmitters (serotonin, dopamine and norepinephrine)

Some of the most important actions of histamine involve regulation of neurotransmitters.  Release of acetylcholine, norepinephrine and serotonin are all controlled in part by histamine levels.  Injection of histamine into the hypothalamus increased metabolism of norepinephrine and serotonin, while dopamine metabolism increased in some places and not in others.  Medications that block the H1 receptor increase dopamine release.  Histamine stimulates prolactin release via the H2 receptor, which in turn inhibits dopamine production.  Histamine can locally increase the concentration of norepinephrine.

Serotonin is a neurotransmitter.  This means that cells nerve cells use this to communicate.  Most of the serotonin in the body is found in the GI tract, where it controls the way the intestine moves food through it.  However, one study indicated that as much as 40% of serotonin in the human body could originate in mast cells.  Serotonin is metabolized to 5-HIAA, which can be tested for as a sign of mast cell activation.
Serotonin released in the GI tract eventually enters the blood stream. On its way to the blood stream, it is taken up by platelets and later used in clotting.   Serotonin is released when eating, which decreases dopamine release and decreases appetite.  If the food consumed is irritating to the GI tract, more serotonin is secreted to move it through the gut faster.  In these situations, the serotonin cannot be fully taken up by platelets and enters the blood stream as free serotonin.  When this happens, it stimulates vomiting.  Some foods contain serotonin, but it does not cross the blood brain barrier and thus does not affect brain chemistry. 
Mast cells contain dopamine, a hormone and neurotransmitter.  This chemical is most often associated with reward seeking behavior, including addiction behaviors.  It also has other important roles, including motor functions.  Mast cell activation causes depletion of dopamine as frequent degranulation causes a decrease in dopamine production by these cells.   Dopamine can be converted to norepinephrine.
In blood vessels, dopamine inhibits norepinephrine release and acts as vasodilator.  Dopamine also increases sodium excretion and urine output, reduces insulin production, reduces GI motility, protects intestinal mucosa and reduces activity of lymphocytes.  It is responsible for cognitive alertness.  If you consider that high histamine levels can decrease dopamine levels, this means that in a mast cell patient, low dopamine levels might cause decreased urine output, increased GI motility and overactivation of white blood cells.  Additionally, low dopamine can translate into higher than normal norepinephrine levels, which could be the link between mast cell disease and POTS.  Brain fog and decreased alertness are effects of low dopamine.
Defective transmission of dopamine is also found in painful conditions like fibromyalgia and restless legs syndrome, associated with mast cell disease.  Activation of D2 dopamine receptors causes nausea and vomiting.  Metoclopramide is a D2 inhibitor and achieves its anti-nausea effects through this mechanism. (Note: metoclopramide can inhibit histamine metabolism and for this reason is not recommended for mast cell patients.)  Some dopaminergic drugs like clozapine, bromocriptine and haloperidol inhibit mast cell degranulation.
Norepinephrine is responsible for concentration and vigilance.  It also increases vascular tone by action on alpha adrenergic receptors.  Norepinephrine is important in the fight or flight response, directly increasing heart rate, triggering release of glucose, increasing blood flow to skeletal muscle and increasing brain oxygen supply.  Interestingly, fasting increases norepinephrine for days.  Glucose intake, but not carbohydrate or protein intake, also increases norepinephrine.  Increased histamine can cause increases in norepinephrine production and secretion.