Chromogranin A

Chromogranin A is a protein secreted in several environments. While it is primarily released in the adrenal medulla with catecholamines (norepinephrine, epinephrine, dopamine, and others), CgA is often found stored in the granules of endocrine cells in the GI tract. CgA is the precursor molecule for several active molecules. Vasostatin-1 and -2 are involved in regulation of various effects of the cardiovascular system, including blood pressure and stroke volume, by opposing the action of catecholamines. Catestatin decreases release of catecholamines. Pancreastatin decreases insulin secretion. A number of other molecules are also derived from CgA.

Chromogranin A and its derivatives are biomarkers for several conditions. 60-80% of neuroendocrine tumor patients demonstrated elevated chromogranin A. A connection with Alzheimer’s disease has recently been reported. Rheumatoid arthritis and lupus patients may have elevated CgA as a result of increased tumor necrosis factor. Various forms of cancer, kidney disease, and elevated cortisol can also impact chromogranin A level.

Elevated CgA has also been linked to a number of inflammatory GI conditions. 30-50% of IBD patients with active disease have elevated serum CgA. In ulcerative colitis, fecal chromogranins were elevated but not correlated with disease activity. Conflicting results have been seen in patients with Crohn’s disease. Some studies have reported an increased amount of CgA containing cells in patients with IBS.

There are a number of methods for quantifying chromogranin A. Proton pump inhibitors and H2 antihistamines can yield false positive results. A study compared several commercial kits for measuring chromogranin A and found that the radioimmunoassay (RIA) kit was most likely to be accurate with a sensitivity of 93% and specificity of 85%. This means that 93% of the time, this kit properly identified patients with high CgA as having high CgA, while 85% of the time, it properly identified patients with normal CgA as having normal CgA. Currently, there are multiple test methods for quantifying serum and plasma CgA with no central standardization.

Chromogranin A is a constituent of granules in rat mast cells. Tumor necrosis factor is a mediator released by mast cells and may also influence the levels of chromogranin A in mast cell patients. One study found that 31.5% of patients with mast cell activation disease (in a cohort mostly composed of MCAS patients) demonstrated elevation of serum CgA. This same study concluded that plasma heparin and 24 urine testing for prostaglandin D2 and 9a,11b-prostaglandin F2 were the most sensitive markers for mast cell activation with other mediators being less effective.

References:

Gut P, et al. (2016) Chromogranin A – unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Arch Med Sci, 12(1): 1-9.

Wernersson S, Pejler G. (2014). Mast cell secretory granules: armed for battle. Nature Reviews Immunology, 14: 478-494.

D’Amico MA, et al. (2014) Biological function and clinical relevance of chromogranin A and derived peptides. Endocrin Connect, 3(2):R45-54.

Mazzawi T, et al. (2015) Increased chromogranin A cell density in large intestine of patients with irritable bowel syndrome after receiving dietary guidance. Gastroenterology Research and Practice, Article ID 823897.

Zenker N, Afrin LB. (2015) Utilities of various mast cell mediators in diagnosis mast cell activation syndrome. Blood, 126:5174.

Massironi S, et al. (2016). Chromogranin A and other enteroendocrine markers in inflammatory bowel disease. Neuropeptides, xxx, xxx-xxx.

Interplay between mast cells and hormones: Part 5 of 8

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

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

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.

 

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.

Interplay between mast cells and hormones: Part 2 of 8

Hormone Location released Major functions Interaction with mast cells Reference
Beta endorphin Pituitary Inhibits pain signaling In two studies, beta endorphin was shown to induce histamine release from mast cells; however, this phenomenon has not been seen by other researchers.

Sensation of pain activates mast cells and can also trigger endorphin release, so interplay between endorphins and mast cells is possible.

Kimura T, et al. Intradermal application of nociception increases vascular permeability in rats: the possible involvement of histamine release from mast cells. European Journal of Pharmacology 2000: 407, 327-332.
Brain natriuretic peptide (BNP) Heart Reduce systemic vascular resistance and water, sodium and fat in blood, decreasing blood pressure

Decrease cardiac output

Vasodilator

Relax smooth muscle of airway

BNP directly activates mast cells in a dose dependent fashion. Yoshida H, et al. Histamine release induced by human natriuretic peptide from rat peritoneal mast cells. Regulatory Peptides 1996: 61, 45-49.
Calcidiol/ Vitamin D3 (inactive) Skin Inactive form of vitamin D3 Vitamin D decreases IgE dependent mast cell activation and cytokine production in a dose dependent fashion.

 

 

Yip KH, et al. Mechanisms of vitamin D3 metabolite repression of IgE-dependent mast cell activation. Journal of Allergy and Clinical Immunology 2014: 133 (5), 1356-1364.
Calcitonin Thyroid Stimulates bone construction

Promotes retention of calcium in bone

One report in 1994 noted that serum calcitonin was increased in a patient with SM. Yocum MW, et al. Increased plasma calcitonin levels in systemic mast cell disease. Mayo Clin Proc 1994: 69 (10), 987-990.
Calcitriol/ Vitamin D3 Kidney Promote absorption of calcium and phosphate in GI tract

Inhibit release of parathyroid hormone in kidneys

Vitamin D decreases IgE dependent mast cell activation and cytokine production in a dose dependent fashion.

 

 

Yip KH, et al. Mechanisms of vitamin D3 metabolite repression of IgE-dependent mast cell activation. Journal of Allergy and Clinical Immunology 2014: 133 (5), 1356-1364.
Cholecystokinin Small intestine Release of digestive enzymes from pancreas and bile from gallbladder

Suppresses hunger

Stimulates vagus nerve

Decreases gastric emptying and GI motility

Unclear role in medication tolerance and withdrawal

The form of CCK most predominant in intestine (CCK-33) stabilizes mast cells.

May have a role in preventing mast cell degranulation as a response to food.

Vergara P, et al. Neuroendocrine control of intestinal mucosal mast cells under physiological conditions. Neurogastroenterology 2002: 14(1), 35-42.
Corticotropin releasing hormone (CRH) Hypothalamus Stimulate ACTH release from pituitary CRH binds to mast cell receptors CRHR-1 and CRHR-2 causing release of VEGF but not histamine, tryptase or IL-8.

CRH is also released by mast cells.

Theoharides TC, et al. Mast cells and inflammation. Biochim Biophys Acta 2012: 1822(1), 21-33.
Cortisol and other glucocorticoids Adrenal gland (cortex) Breaks down fat in adipose tissue

Drives production of glucose, epinephrine and norepinephrine

Inhibits immune action and inflammation, protein production, and glucose transfer to muscle and adipose tissue

Cortisol has a wide range of other effects

Glucocorticoids inhibit mediator production in several ways.

Decreases prostaglandin production by decreasing levels of COX-2, an enzyme that makes prostaglandins.

Decreases production of leukotrienes, prostaglandins and thromboxanes by increasing anti-inflammatory molecules.

Triggers release of annexin-1, an anti-inflammatory molecule that is also involved in the mast cell stabilizing mechanism of cromolyn.

Lowers bradykinin levels, decreasing swelling.

Directly interferes with production and secretion of cytokines.

The role of 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.

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Mol Cell Endocrinol 2013: 380, 119-126.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Author’s note: I tried to hit the high notes here but cortisol has a massive range of effects on immune function, including mast cells, so the next post in this series will be dedicated just to cortisol and the effects on mast cells.

 

 

 

 

Mood disorders and inflammation: High cortisol and low serotonin (Part 2 of 4)

There are multiple suspect pathways for causation of mood dysregulation in the setting of inflammation. One well described model hinges upon the ability of inflammatory mediators to impact the HPA axis, a system of hormone release that drives many physiologic functions in addition to the stress response.  Briefly, the central pathway of the HPA axis is that CRH causes production of ACTH, which causes production of cortisol, a stress hormone and a very potent anti-inflammatory under most circumstances.  Many molecules can affect the signaling of the HPA axis and contribute to inappropriate hormone regulation.

IL-1, IL-6, TNF and IFN-a are all inflammatory mediators released by mast cells and other cells. These mediators all activate the HPA axis, resulting in high production of CRH, ACTH and cortisol via a series of intertwined mechanisms. At the same time, inflammation also makes cortisol less effective.  There are several ways for this to occur. Inflammation can cause cells to make fewer receptors for cortisol, meaning that no matter how much cortisol is made, only a small fraction will be able to act on cells.  Persistently high cortisol levels decrease production of other anti-inflammatory molecules and molecules that mediate the anti-inflammatory action of cortisol.  High cortisol also tells the HPA axis that it doesn’t need to make more cortisol, so even though more may actually be necessary, your body doesn’t know that.

All of these factors coalesce to form a reality where cortisol may be elevated but with little anti-inflammatory effect because of the changes I mentioned above. High cortisol is associated with mood symptoms.

Decrease of serotonin activity is also seen in mood disorders. Tryptophan is a precursor to serotonin, a hormone and neurotransmitter that heavily regulates mood.  Cortisol increases the activity of a molecule called tryptophan 2,3-dioxygenase (TDO), which removes the amino acid tryptophan from the pool of molecules to break down. Inflammatory molecules like interferon increase activity of the enzyme IDO, which decreases serotonin production.  IDO breaks down tryptophan to molecules that cannot be made into serotonin, such as kynerenin and quinolonic acid.  These metabolites have been observed as elevated in models of depression and anxiety.

Another way that inflammatory mediators affect the action of serotonin is to hasten its degradation. Both TNF and IL-6 increase the breakdown of serotonin to 5-HIAA.

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.

Leptin: the obesity hormone released by mast cells

Leptin is a hormone that is primarily secreted by adipose tissue, but is also produced and released by mast cells. In turn, mast cells also have leptin receptors. Leptin is primarily known for its action of part of the hypothalamus to inhibit the hunger response. Importantly, the body responds forcefully to leptin levels by engaging both biological and behavioral mechanisms to conserve energy. It is seen by researchers as less of a “hunger satiety” signal and more of a “starvation” signal.

Patients with obesity often have higher circulating levels of leptin than those without obesity. This occurs because leptin is secreted by adipose tissue, which obese patients have in higher amounts due to their higher percentage of body fat. These people seem to be resistant to the chemical action of leptin, possibly through a change in activity of leptin receptors in the hypothalamus. Some studies suggest that in obese patients, less leptin leaves the blood stream and crosses into the brain.

Leptin is now known to have a variety of other effects on the body, including modulating the immune system. It activates inflammatory cells, promotes T cell responses and mediates production of TNF, IL-2 and IL-6. In many inflammation models, cells express more leptin receptors than usual. In diet induced obese mice, mast cells have been observed to store and secrete TNF. In immune mediated diseases like autoimmune diseases, circulating levels of leptin are increased, and this in turn translates to higher levels of inflammatory cytokines.

Interestingly, leptin suppresses signals from the IgE receptor to make mediators. In leptin receptor deficiency models, magnified IgE anaphylaxis was observed. Leptin also seems to control the number of mast cells through some unclear mechanism. In leptin deficient mice, mast cell density is significantly higher in abdominal lymph nodes and fat deposits.

Leptin influences the release of many other molecules, including ghrelin. Ghrelin is the “hunger hormone,” released in the stomach and possibly elsewhere. It stimulates the hunger response in the body and also acts on the hypothalamus. The relationship between leptin and ghrelin is very complex and still being elucidated. However, it is thought that high levels of circulating leptin suppress secretion of ghrelin. This is especially of interest in inflammatory conditions as ghrelin suppresses production of a number of inflammatory markers, including TNF, IL-8, MCP-1, IL-1b, IL-6, CRP and others. This effect is so pronounced that it is being investigated as a treatment option for many conditions. Ghrelin has also been observed in one study in induce mast cell activation through a receptor independent pathway.

 

References:

Baatar D, Patel K, Taub DD. The effects of ghrelin on inflammation and the immune system. Mol Cell Endocrinol. 2011 Jun 20; 340(1): 44-58.

Hirayama T, et al. Ghrelin and obestatin promote the allergic action in rat peritoneal mast cells as basic secretagogues. Peptides. 2010 Nov;31(11):2109-13

Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan; 8(1): 21-34.

Taildeman J, et al. Human mast cells express leptin and leptin receptors. Histochem Cell Biol. 2009 Jun; 131(6): 703-11.

Patricia Fernández-Riejos, Souad Najib, Jose Santos-Alvarez, Consuelo Martín-Romero, Antonio Pérez-Pérez, Carmen González-Yanes, and Víctor Sánchez-Margalet. Role of Leptin in the Activation of Immune Cells. Mediators of Inflammation, Volume 2010 (2010), Article ID 568343, 8 pages.

Altintas et al. Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice. Lipids in Health and Disease 2012, 11:21