July 2016

Interplay between mast cells and hormones: Part 5 of 8

by Lisa Klimas
July 7, 2016July 16, 2016

Hormone	Location released	Major functions	Interaction with mast cells	Reference
Inhibin	Testes, ovaries, placenta, pituitary	Inhibits production of FSH	No known interaction with mast cells
Insulin	Pancreas	Promotes transfer of glucose from blood to liver and muscle Promotes production of glycogen in liver Promotes liberation of glucose stores in liver	Increases growth and survival of mast cells Increases degranulation and mediator release	Lessmann E, et al. Insulin and insulin-like growth factor-1 promote mast cell survival via activation of the phosphatidylinositol-3-kinase pathway. Experimental Hematology 2006: 34(11), 1532-1541.
Insulin like growth factor	Liver	Modulates cell growth and development Behaves like insulin	Increases growth and survival of mast cells Increases degranulation and mediator release	Lessmann E, et al. Insulin and insulin-like growth factor-1 promote mast cell survival via activation of the phosphatidylinositol-3-kinase pathway. Experimental Hematology 2006: 34(11), 1532-1541.
Leptin	Adipose tissue	Decrease of appetite	Activates inflammatory cells and T cell responses Increases production of TNF, IL-2 and IL-6 Decreases mediator production due to activation of IgE receptor Suppresses secretion of ghrelin	Taildeman J, et al. Human mast cells express leptin and leptin receptors. Histochem Cell Biol 2009: 131(6), 703-711.
Luteinizing hormone (LH)	Pituitary	Stimulates ovulation and formation of corpus luteum Stimulates testosterone production	Histamine decreases LH release by acting at H1 receptor. Histamine increases release of luteinizing hormone releasing hormone (LHRH), also by acting at H1 receptor.	Miayke A, et al. Involvement of H1 histamine receptor in basal and estrogen-stimulated luteinizing hormone-releasing hormone secretion in rats in vitro. Neuroendocrinology 1987: 45(3), 191-196. Pontiroli AE, et al. The effect of histamine and H1 and H2 receptors on prolactin and luteinizing hormone release in humans: sex differences and the role of stress. J Clin Endocrinol Metab 1981: 52(5), 924-928.
Melanocyte stimulating hormone (MSH)	Pituitary	Stimulates melanin production and release Increases during pregnancy	MSH can induce apoptosis in mast cells Dose dependent increase in histamine relief, but not in IL-1, IL-6, IL-8, TGFb or TNF	Sarkar A, et al. alpha-Melanocyte-stimulating hormone induces cell death in mast cells: involvement of NF-kappaB. FEBS Lett 2003: 549(1-3), 87-93. Grutzkau A, et al. alpha-Melanocyte stimulating hormone acts as a selective inducer of secretory functions in human mast cells. Biochem Biophys Res Commun 2000: 278(1), 14-19.
Melatonin	Pineal gland, immune system	Induces sleep and lowers body temperature	Mast cells produce and release melatonin regardless of activation state	Maldonado MD, et al. Evidence of melatonin synthesis and release by mast cells. Possible modulatory role on inflammation. Pharmacol Res 2010: 62(3), 282-287.

Interplay between mast cells and hormones: Part 4 of 8

by Lisa Klimas
July 5, 2016July 16, 2016

Hormone	Location released	Major functions	Interaction with mast cells	Reference
Ghrelin	Stomach, jejunum, duodenum, colon, brain, lungs, liver, adipose tissue, placenta, lymphatic system	Stimulate appetite Can cross BBB	Induced mast cell degranulation Dose dependently induced histamine release Inhibits many inflammatory molecules, like TNF, IL-8, MCP-1, IL-1b, IL-6, CRP, IL-12, VCAM-1, MMP2, MMP9, GM-CSF and IL-17 Opposes action of leptin, a mast cell mediator Level is increased by lack of sleep, promoting excessive hunger.	Hirayama T, et al. Ghrelin and obestatin promote the allergic action in rat peritoneal mast cells as basic secretagogues. Peptides 2010: 31(11), 2109-2113. Baatar D, et al. The effects of ghrelin on inflammation and the immune system. Molecular and Cellular Endocrinology 2011: 340(1), 44-58.
Glucagon	Pancreas	Regulates amount of available glucose Triggers breakdown of glycogen and production of glucose in liver, raising blood sugar Released when blood sugar is too low Can increase level of cAMP in myocardium to overcome effect of beta blockers Anecdotal reports that glucagon may be able to relax esophagus sphincter to pass impacted food	In anaphylaxis patients on beta blockers, glucagon can be used to reduce resistance to epinephrine and increase blood pressure May be considered to treat Kounis Syndrome where epinephrine is contraindicated Histamine H3 receptor may regulate glucagon release from pancreas	Nakamura T, et al. Role of histamine H3 receptor in glucagon secreting aTC1.6 cells. FEBS Open Bio 2015: 5, 36-41. Thomas M, Crawford I. Glucagon infusion in refractory anaphylactic shock in patients on beta blockers. Emerg Med J 2005: 22, 272-276.
Glucagon-like peptide 1 (GLP-1)	Small intestine	Increases release of insulin and nausea Decreases release of glucagon, desire to eat and amount of food consumed Increases anxiety	Possible relationship between GLP-1 and histamine in the brain, but still unclear GLP-1 level is modulated by leptin, a mast cell mediator Increases ACTH and cortisol	Gotoh K, et al. Glucagon-like peptide-1, corticotropin-releasing hormone, and hypothalamic neuronal histamine interact in the leptin-signaling pathway to regulate feeding behavior. FASEB J 2005: 19(9), 1131-1133.
Gonadotropin releasing hormone	Hypothalamus	Stimulate FSH and LH release from pituitary Part of HPG axis Drive secondary sex characteristics Regulate sex hormone release	Histamine induces GnRH release in some studies	Noris G, et al. Histamine directly stimulates gonadotropin-releasing hormone secretion from GT1-1 cells via H1 receptors coupled to phosphoinositide hydrolysis. Endrocrinology 1995: 136(7), 2967-2974.
Growth hormone releasing hormone	Hypothalamus	Stimulate growth hormone release from pituitary Regulates bone growth Regulates metabolism of proteins, carbohydrates and lipids	Induces mast cell degranulation and release of serotonin and histamine, causing low blood pressure	Macia RA, et al. Hypotension induced by growth hormone releasing peptide is mediated by mast cell serotonin release in the rat. Toxicology and Applied Pharmacology 1990: 104(3), 403-410.
Hepcidin	Liver	Decreases iron absorption in intestines Decreases iron release by macrophages	Chronic inflammation causes elevated hepcidin, making iron less available. This is called anemia of chronic inflammation.	Weiss G. Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Seminars in Hematology 2015: 52(4), 313-320.
Human chorionic gonadotropin (HCG)	Placenta	Maintains hormone release in ovaries during pregnancy Inhibition of immune defense against fetus	Not known to directly affect mast cell activation or histamine release	Schumacher A, et al. Endocrine factors modulating immune responses in pregnancy. Front Immunol 2014: 5, 196.

Interplay between mast cells and hormones: Part 3 of 8

by Lisa Klimas
July 3, 2016July 16, 2016

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.

Mood disorders and inflammation: Neurologic effects and treatment (Part 4 of 4)

by Lisa Klimas
July 1, 2016July 16, 2016

TNF blockers like Enbrel and infliximab can lower depression independent of improvements with physical symptoms. 62% of patients with treatment resistant depression saw improvement on infliximab versus 33% with standard therapies. Infliximab also improved sleep, allowing patients to stay asleep longer. Infliximab successfully improved depression symptoms in patients with inflammatory disease as well as controls who had elevated CRP and TNF but not on controls with normal CRP and TNF. Patients who were not effectively treated with SSRIs were found to have higher IL-6 and TNF.

Chronic inflammation can cause structural and functional changes in the brain, interfering with its ability to make new connections and damaging existing function. Activation of microglial cells in the nervous system is associated with maladaptive behaviors and decreased brain function seen in bipolar disorder, major depressive disorder and other mood conditions. They also protect neurologic function in multiple sclerosis, Huntington’s and Alzheimer’s. Minocycline, an antibiotic, also has significant anti-inflammatory and neuroprotective effects.

In some encephalitis models, DMARDs can actually restore stem cells of the nervous system, reducing tissue and myelin damage. DMARDs, often used for autoimmune diseases, improve mood symptoms in rheumatoid arthritis patients. They can also mitigate hyperactivity from amphetamines. Clinical trials are currently investigating the full effects of these medications on psychiatric conditions.

Mood stabilizers often have anti-inflammatory effects. In bipolar disorder patients, lithium and valproate decreased IL-6. Medications that act on serotonin and dopamine receptors decrease production of inflammatory molecules like TNF, IL-6 and PGE2. Escitalopram, an SSRI antidepressant, can decrease cortisol production and IL-11. ACTH production can be induced by fluoxetine.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.