The Sex Series – Part Six: Male pelvic dysfunction and mast cells

Chronic pelvic pain syndrome (CPPS) affects about 15% of male patients and 90% of patients with chronic prostatitis. Patients with these conditions experience pain in the pelvis, abdomen and genitalia, as well as urinary tract symptoms without evidence of infection. Pain can be intermittent or constant, and can interfere with daily activities including sitting, standing, urination and defecation.

CPPS also causes sexual symptoms. Painful ejaculation, erectile dysfunction, and other types of ejaculation dysfunction are all common in this patient group.  In one study, 40% of patients with CPPS were found to have erectile dysfunction.  In another, 72% of patients reported either erectile dysfunction or difficulty with ejaculation.

Pelvic floor dysfunction is a component of CPPS. Many of these patients have abnormally tense pelvic floor muscles, which can cause muscle spasm and obstruct bloodflow. CPPS patients are more likely than healthy controls to have vascular dysfunction associated with nitric oxide level. In a group of 146 patients with CPPS and verified pelvic floor spasm, 56% experienced painful ejaculation.  Visceral and myofascial pain and spasm of the muscles in the pelvic floor contribute to CPPS.  While pelvic floor dysfunction has been well researched for female patients, there are far fewer studies on pelvic floor dysfunction in men.  Biofeedback and pelvic floor physical therapy can resolve issues with erectile dysfunction and other sexual issues.

IL-17, expressed by special T cells called Th17 cells, is required to develop CPPS-like conditions in animal models. IL-17 triggers mast cell degranulation and secretion of many inflammatory molecules.  A number of mast cell mediators are elevated in patients with CPPS. IL-1b, TNF, IL-6 and IL-8 are higher in seminal fluid of these patients.  CCL2 and CCL3 expression is also increased. In the prostate of animals with a CPPS model, TNF, IL-17a, IFN-γ and IL-1b are all increased.

Tryptase has been found to induce pelvic pain. Levels of tryptase and carboxypeptidase A3 are higher in CPPS patients than in healthy controls.  Tryptase binds to a receptor called PAR2.  When tryptase binds to this PAR2 receptor, it is thought that it makes nerves oversensitive. If the PAR2 receptor is blocked, pelvic pain is mitigated.  In animal models where they cannot make tryptase-like products, pelvic pain does not develop in CPPS.

Nerve growth factor (NGF) is a mast cell mediator that has been implicated in CPPS. It is elevated in seminal plasma of CPPS patients and directly correlates with pain level. It is thought that NGF makes the peripheral nerves oversensitive and causes more nerve cells than usual to be present. NGF and tryptase were elevated in prostate secretions of most CPPS patients in a small patient group. Of note, NGF release occurs and increases weeks after initial symptoms.

In animal models, injecting cetirizine (H1 antihistamine) into the peritoneal cavity decreased pain by about 13.8%; ranitidine (H2 antihistamine), 6.1%; cromolyn, 31.4%. A combination of all three decreased pain by 69.3%. When cromolyn and cetirizine were used together, larger pain relief was achieved than when used individually, but this was not seen when using ranitidine and cromolyn together.  These data suggest that H2 signaling is not a major contributor in chronic pelvic pain in male patients.

Pelvic floor dysfunction is also common in heritable connective tissue diseases and is often present in hypermobile patients.

References:

Done JD, et al. Role of mast cells in male chronic pelvic pain. Journal of Urology 2012: 187, 1473-1482.

Roman K, et al. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome. Pain 2014: 155 (7), 1328-1338.

Cohen D, et al. The role of pelvic floor muscles in male sexual dysfunction and pelvic pain. Sex Med Rev 2016; 4, 53-62.

Murphy SF, et al. IL17 mediates pelvic pain in experimental autoimmune prostatitis (EAP). PLoS ONE 2015, 10(5) : e0125623.

 

Glossary of mast cell related terms: P-Z

Parasympathetic nervous system: Part of the autonomic nervous system.  Regulates digestion and other functions.

Prostaglandin D2 (PGD2): The dominant prostaglandin produced by mast cells.

9a,11b-PGF2: a breakdown product of prostaglandin D2; can be measured to assess level of mast cell activation

Platelet activating factor (PAF): a mast cell mediator that correlates with severity of anaphylaxis; induces degranulation and release of leukotrienes and prostaglandins

Postural orthostatic tachycardia (POTS): increase of 30 bpm or more when standing in the absence of orthostatic hypotension.

Premedication: taking medication in advance of an event in order to suppress an undesirable reaction during the event, such as premedicating before surgery

Pre-stored: as relates to mast cell biology, mediators that are made inside the cell and stored in granules to be released at a later time

Progenitor cell: a cell that develops into another type of cell

Proliferation: growth and expansion of a cell population

Prostaglandin: a type of eicosanoid with wide ranging biological effects; PGD2 is the prostaglandin most abundantly produced by mast cells

Protracted anaphylaxis: a long episode of anaphylaxis symptoms despite treatment

Rare disease: a disease that affects only a small amount of people in a population; in the US, defined as affecting 200,000 people or less in the US

Rebound: a resurgence of symptoms after quelling symptoms earlier

Receptor: a protein on the outside of cells that bind specific molecules, causing a specific action to occur

Secretion: the release of molecules from inside the cell to the outside environment without degranulation

Sensitization: production of IgE specific to an allergen without obvious allergic reaction to the allergen

Serotonin: a neurotransmitter released by a number of cell types, including mast cells

Smouldering systemic mastocytosis (SSM): a form of SM in which organ damage and failure could eventually occur; diagnosed when someone with SM has two or more B findings

Splenomegaly: swelling of the spleen

Stem cell factor (SCF): a mast cell growth factor; SCF binds to CKIT and tells mast cells to stay alive and make more mast cells

Sympathetic nervous system: Part of the autonomic nervous system.  Controls the fight or flight response

Systemic mastocytosis (SM): a proliferative mast cell disease in which too many mast cells are produced

Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): co-occurrence of SM with another proliferative blood cell disorder, such as essential thrombocythemia or chronic myelogenous leukemia

Tachycardia: rapid heartbeat

Third spacing: when fluid is forced out of a place the body can use it and becomes trapped, such as ascites or angioedema

TLR: toll like receptor; receptors on the outside of many cells (including mast cells) that activate immune response to infections

Telangiectasia macularis eruptive perstans (TMEP): a less common form of cutaneous mastocytosis.  Found almost exclusively in adults.

Tryptase: a mast cell mediator; when tested outside of a symptomatic episode, it is used to measure the baseline amount of mast cells present ; when tested during a symptomatic episode, it can be used to identify mast cell activation

Urticaria pigmentosa (UP): also called maculopapular cutaneous mastocytosis (MPCM).  The most common form of cutaneous mastocytosis.

Urticaria: hives

Wheal and flare response: a reaction marked by redness and raised, taut skin due to histamine release

Glossary of mast cell related terms: M-O

Mast cell: white blood cells with important roles in allergy, anaphylaxis and immune defense that live in tissues and only briefly circulate in the blood; also called mastocytes

Mast cell activation: a change in mast cell behavior that occurs following exposure to a trigger that may indicate allergy or infection; a state in which mast cells release mediators, both through degranulation and through secretion; in some instances, culminating in anaphylaxis

Mast cell disease: a disease that occurs due to fundamental error in mast cell proliferation or activation physiology

Mast cell disorder: used synonymously with mast cell disease

Mast cell leukemia: a very aggressive mast cell disease marked by massively excessive proliferation of mast cells, culminating in progressive organ failure

Mast cell sarcoma: a very aggressive mast cell disease that presents as a connective tissue tumor and progresses to mast cell leukemia

Mast cell stabilizer: a medication that decreases the likelihood of mast cell degranulation and mediator release

Mastocytic enterocolitis: the phenomenon of having too many mast cells in the GI tract; originally described as more than 20 mast cells/ high power field, but there is no consensus on how many mast cells in a field is too many

Mastocytoma: a benign mast cell tumor. Most frequently occurs on skin, but can occur elsewhere in the body.

Mast cell activation disease (MCAD): usually a catchall term for mast cell diseases, although some people exclude cutaneous mastocytosis from this category

Mast cell activation disorder (MCAD): an alternate term for mast cell activation syndrome (MCAS); a non-proliferative mast cell disease that is usually diagnosed by detecting an elevation in mast cell mediators

Mast cell activation syndrome (MCAS): a non-proliferative mast cell disease that is usually diagnosed by detecting an elevation in mast cell mediators; occurs secondary to a known condition or idiopathically, in which no primary condition is identified; “primary” mast cell activation syndrome has its own name, MMAS

Mediator: a molecule released from a cell that has effects on the environment outside the cell; mast cells release dozens of mediators

Monoclonal mast cell activation syndrome (MMAS) : a mast cell disease diagnosed when a patient meets some criteria for SM but not enough for an SM diagnosed

Monophasic anaphylaxis: an anaphylactic event in which symptoms resolve following administration of medication and do not recur at a later time

Mutation: a change in the genetic sequence that can affect the way a gene is expressed, or in the way its gene product is made or functions

Myeloid: concerning cells that develop into granulocytes, monocytes, platelets or erythrocytes

Myeloproliferative neoplasm: a disorder caused by aberrant proliferation of a myeloid cell line, such as SM, myelofibrosis, essential thrombocythemia or polycythemia vera, among others

Neoplasm: an abnormal cell

N-methylhistamine: a breakdown product of histamine; can be tested for to assess mast cell activation

Oral allergy syndrome: An IgE reaction to raw fruits and vegetables that causes itching and swelling in the mouth and throat.

Orthostatic hypotension (OH): reduction of systolic blood pressure of more than 20 mm Hg or diastolic blood pressure of more than 10 mm Hg within three minutes of standing.

Orthostatic intolerance (OI): symptoms that occur when transitioning to a standing position

Naturally occurring mast cell stabilizers: Part 4

I mentioned resveratrol in the previous post under its broad classification as a phenol.  Looking more narrowly, resveratrol is a derivative of stilbene.  It is found in several foods, including grapes and berries like blueberries and raspberries.  Resveratrol can form oligomers, in which several of the same molecule are connected together.  One such oligomer is Gnetin H.  This product is isolated from Paeonia anomala and is used in Mongolian Chinese medicine.  It has been found to significantly impair mast cell degranulation and is effective at lower doses than resveratrol.  Gnetin H also decreased histamine secretion and production of TNF and IL-4, as well as COX-2 and PGE2 (not a typo, prostaglandin E2).

Polydatin is a precursor to resveratrol.  In a rat model, administration of polydatin was found to make the small intestine mucosa much less “leaky”.  It also inhibited hypersensitivity in the small intestine.  Importantly, it decreased degranulation by as much as 65% (determined by examining tissue with toluidine blue staining), and decreased histamine in both serum and intestinal mucosa.  Degranulation involves changes in calcium inside the mast cell and treatment with polydatin interfered with this process.  It also interrupted production of IgE by suppressing IL-4 secretion.  In another paper, polydatin was also found to suppress anaphylaxis in the mouse model of passive cutaneous anaphylaxis.

Hydroxytyrosol is a phenol derived from olive oil and olive leaves.  In nature, it occurs in the form of oleuropein, which can be broken down to hydroxytyrosol.  In a study that used β-hexosaminidase as a  marker for mast cell degranulation, both hydroxytyrosol and oleuropein inhibited activation in cells at high concentrations. This is promising but future research is needed.

In mouse and human mast cells, hypothemycin was found to interfere with activation of the CKIT receptor and the IgE receptor (FceRI).  This resulted in suppression of degranulation and production of cytokines, including IL-4.  This product was originally extracted from a mushroom of the Hypomyces genus.

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.

Kim M, et al. Gnetin H isolated from Paeonia anomala inhibits FceRI-mediated mast cell signaling and degranulation. J Ethnopharmacol 2014 Jul 3; 154(3): 798-806.

Yang B, et al. Polydatin attenuated food allergy via store-operated calcium channels in mast cell. World J Gastroenterol 2013 Jul 7; 19(25): 3980-3989.

Yuan M, et al. Polydatin (PD) inhibits IgE-mediated passive cutaneous anaphylaxis in mice by stabilizing mast cells through modulating Ca2+ mobilization. Toxicol Appl Pharmacol 2012 Nov 1; 264(3): 462-469.

Persia FA, et al. Hydroxytyrosol and oleuropein of olive oil inhibit mast cell degranulation induced by immune and non-immune pathways.  Phytomedicine. 2014 Sept 25; 21(11): 1400-1405.

Naturally occurring mast cell stabilizers: Part 3

Coumarins are compounds that occur naturally in a number of plant species.  Several medications are derived from coumarins, including several anticoagulants, such as warfarin. They are notable for being fragrant.  Coumarin increases resorption of edema fluids.

Scopoletin is a coumarin present in the root structures of several species, including Urtica dioica (stinging nettle), Scopolia japonica (Japanese belladonna), chicory and passion flower.  In human mast cells, scopoletin interferes with production of TNF, IL-6 and IL-8.  It was found to inhibit NF-kB, which participates in the inflammatory response.

Artekeiskeanol A is a coumarin extracted from Artemisa keiskeana.  In traditional medicine systems, it is sometimes used to treat rheumatoid arthritis.  It suppressed degranulation, decreased production of TNF and IL-13.  Selinidin, a coumarin found in Angelica keiskei, suppresses IgE-initiated degranulation and decreases production of LTC4 and TNF. Rottlerin from the tree Mallotus philippensis attenuates IgE activation, degranulation of at least airway mast cells, and histamine release.

Cinnamic acid is a coumarin that decreased antigen stimulated degranulation in basophils, but similar action has not been recorded in mast cells.  It is most commonly extracted from cinnamon oil. A furanocoumarin found in Angelica dahurica inhibits action of COX-2 and 5-LO, decreasing production of PGD2 and LTC4, in addition to preventing degranulation.

Thunberginol A and B from Hydrangeae macrophylla inhibits histamine release from activated mast cells.  Thunberginol A prevents release of TNF and IL-4. In particular, thunberginol B is a potent mast cell stabilizer, suppressing degranulation from IgE or other causes.  It can also suppress production of IL-2, IL-3, IL-4, IL-13, TNF and GM-CSF when triggered by IgE.

Ellagic acid is found in nuts and fruit, such as strawberries, raspberries, pomegranate and walnuts. It interferes with IgE activation of mast cells and decreases release of histamine, TNF and IL-6.

Plant phenols have been reported to have medicinal effects for many years.  Magnolol and honokiol, two substance found in the bark of Magnolia obovata, can interfere with basophil degranulation as well as allergic response more generally.  Resveratrol is a phenol derivative present in berries, peanuts and grapes.  It is a potent supporessor of inflammatory mast cell products, including TNF, IL-6 and IL-8.  It also interferes with the structures required for degranulation and can also interfere with basophil degranulation.

Curcumin is another phenol derivative and is already quite popular in the mast cell community. (Disclaimer: I take turmeric, which contains curcumin.)  Curcumin has well described anti-inflammatory and anti-allergic benefits.  It inhibits mast cell and basophil degranulation and decreases release of IL-4 and TNF.  It also suppresses a popular lab model of allergy, passive cutaneous anaphylaxis.

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Moon PD, et al. Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IkappaB/NF-kappaB signal cascade in the human mast cell line HMC-1. Eur J Pharmacol 2007 Jan 26; 555(2-3): 218-225.

Kishiro S, et al. Selinidin suppresses IgE-mediated mast cell activation by inhibiting multiple steps of Fc epsilonRI signaling. Biol Pharm Bull 2008 Mar; 31(3): 442-448.

Bheekha-Escura, Roy, et al. Pharmacologic regulation of histamine release by the human recombinant histamine-releasing factor. May 1999; 103(5): 937-943.

Hong J, et al. Suppression of the antigen-stimulated RBL-2H3 mast cell activation by Artekeiskeanol A. Planta Med 2009 Nov; 75(14): 1494-1498.

Naturally occurring mast cell stabilizers: Part 2

As discussed in the previous post, many flavonoids can modulate mast cell responses.  Luteolin, a flavone, has been studied for its powerful effects on inflammatory cells.  With prophylactic administration of this molecule, activation of mast cells and T cells can be prevented in a disease model for multiple sclerosis. Luteolin can also inhibit IgE-triggered degranulation as well as production of various mediators.  It is found in many foods, including celery, carrots, and chamomile tea.

Genistein, an isoflavone, prevents IgE-induced degranulation and histamine release.  It is a natural tyrosine kinase inhibitor, mostly activate against EGFR. It can be extracted from Genista tinctoria, also called dyer’s broom.  Several structurally related molecules also have mast cell modulating effects. Amentoflavone, from Ginkgo biloba and St. John’s Wort, decreases histamine release by mast cells. Ginkgetin, derived from Ginkgo biloba leaves, inhibits phospholipase A2, a mast cell mediator, and inhibits production of PGD2 by interfering with the COX-2 enzyme and of LTC4 by interfering with 5-lipoxygenase.

Emodin is an anthraquinone with a long history of use in herbal medicine traditions.  It boasts an array of anti-allergic activity and can inhibit the following IgE induced effects: mast cell degranulation; production of TNF, PGD2 and LTC4; and secretion of TNF and IL-6. It is under investigation for use in type II diabetes, where it can decrease the activity of glucocorticoids in obese animals and may treat insulin resistance.  Emodin can be found in rhubarb, frangula bark and other plants.

A number of other natural molecules also have mast cell stabilizing effects. Epigallocatechin gallate, found in higher quantities in white and green teas, as well as apples, onions and hazelnuts, can inhibit mast cell degranulation and LTC4 secretion.  Xanthones found in the juice and fruit of the purple mangosteen, Garcinia mangostana, decreased histamine release as well as PGD2, LTC4 and IL-6 from mast cells.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Kritas SK, et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents 2013 Oct-Dec; 27(4): 955-959.

Theoharides TC, Kempuraj D, Iliopoulou BP. Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. Adv Exp Med Biol 2007; 601: 423-30.

Son JK, et al. Ginkgetin, a biflavone from Ginkgo biloba leaves, inhibits cyclooxygenases-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells. Biol Pharm Bull 2005 Dec; 28(12): 2181-4.

Lu Y, et al. Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation. Biochem Pharmacol 2011 Dec 1; 82(11): 1700-1708.

Kim DY, et al. Emodin attenuates A23187-induced mast cell degranulation and tumor necrosis factor-a secretion through protein kinase C and IkB kinase 2 signaling. Eur J Pharmacol 2014 Jan 15; 723: 501-506.

Naturally occurring mast cell stabilizers: Part 1

Warning: Naturally occurring molecules can interfere with medications or adversely affect disease state.  Please consult with your managing provider before adding supplements or drastically changing diet.

Flavonoid is a broad term used to describe certain plant derived metabolites. It can be used to refer to a variety of molecules, including isoflavonoids, neoflavonoids and anthoxanthins, which are categorized based on structure.  A number of flavonoids have been shown experimentally to modulate mast cell behavior and function as mast cell stabilizers.

Homoisoflavonone decreases production of PGD2 and leukotrienes B4 and C4 by downregulating COX-2 and 5-LO, the enzymes that make these molecules from arachidonic acid. It also interferes directly with the manufacture of IL-6 and TNF in mast cells stimulated by IgE (the traditional allergy pathway).  Homoisoflavonone can be isolated from bulbs of Cremastra appendiculata, which is commonly called Chinese tulip despite being an orchid.  Chinese tulip is commonly used in Chinese medicine.  Related homoisoflavonoids, extracted from the tuber of Ophiopogon japonicas, mondograss, are anti-inflammatories, possibly by interfering with COX-2 and 5-LO.

Flavonols have been noted for their anti-allergic activity for a number of years.  Morin is a flavonol found in natural sources like Maclura pomifera (Osage orange) and Psidium guajava (guava).  Morin prevents mast cell degranulation and manufacture of cytokines like TNF and IL-4, as well as suppressing IgE activation almost completely at higher doses (please note the study on this used mice so it’s not clear what those dose would be in humans).  Other mast cell active flavonols include quercetin, myricetin, rutin, fisein and kaempferol.

Quercetin downregulates the expression of histidine decarboxylase, the enzyme that modifies histidine, an amino acid, to histamine.  Quercetin also inhibits release of histamine, prostaglandins and leukotrienes.  Additionally, it decreases production and release of IL-1b, IL-6, IL-8 and TNF.  Quercetin was reported to be stronger and more effective at inhibiting mediator release than cromolyn when taken prophylactically, although this has not yet been judged as true by any regulatory body.  Quercetin is found naturally in a number of foods, such as red onion, sweet potato, kale, and many others.  It is also found in small quantities in teas made with Camellia sinensis.  Rutin is a derivative of quercetin, found in citrus fruits, apples, cranberries and others.

Fisetin, kaempferol, myricetin, quercetin and rutin inhibited IgE mediated histamine release and prevented increased concentration of calcium inside mast cells, which is necessary for degranulation.  Fisetin, quercetin and rutin all decreased production of IL-1b, IL-6, IL-8 and TNF. Fisetin, myricetin and rutin all decreased action of NF-kB, which controls the pathway regulating production of cytokines. Myricetin is a particularly effective mast cell stabilizer.  It decreased degranulation and release of TNF and IL-6, but not IL-1b or IL-8.

Flavonols have been evaluated for other medicinal properties aside from mast cell modulation.  Myricetin has been suggested as a treatment for many diseases, including diabetes, while kaempferol affects many molecular pathways, including estrogen signaling.  These molecules occur naturally in a number of plants, including walnuts, onions and red grapes for myricetin; apples, onions, persimmons, strawberries and cucumbers for fisetin; and potatoes, squash, cucumbers, peaches and Aloe vera for kaempferol.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Weng Z., et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity inhumans. PLoS One. 2012; 7(3): e33805.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Lee, YS, et al. Homoisoflavonone prevents mast cell activation and allergic responses by inhibition of Syk signaling pathway. Allergy 2014; 69: 453-462.

 

 

 

 

How to activate mast cells: Receptors and Ligands Master Table (part 3)

Receptor Ligand (molecules that bind to the receptor) Result
Nicotinic acetylcholine receptor Acetylcholine Increases severity of anaphylaxis
NOD1, NOD2 Bacterial products Cytokines; dependent upon ligand
Paired Ig-like receptor B (PIR-B) Inhibitory
Peripheral benzodiazepine receptor Benzodiazepines Inhibits mediator release
Platelet endothelial cell adhesion molecule (PECAM-1) Inhibitory
Progesterone receptor Progesterone Inhibits mediator release
Prostaglandin E receptors, EP2, Prostaglandin E Downregulates IgE mediated response, inhibits prostaglandin and leukotriene production

 

Prostaglandin E receptors, EP3, EP4 Prostaglandin E Increases IgE mediated degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Increases IgE dependent cytokine production

 

Protease activated receptors 1-4 (PAR1-4) Serine proteases (trypsin, tryptase, chymase) Histamine release, mast cell activation
Purinoreceptor P2Y11 ATP Production of prostaglandins and leukotrienes
Purinoreceptor P2Y2 ATP, UTP Production of prostaglandins and leukotrienes
Purinoreceptors P2Y1, P2Y12, P2Y13 ADP Production of prostaglandins and leukotrienes
Sialic acid binding Inhibitory
Sphingosine-1-phosphate S1P1 Sphingosine-1-phosphate Chemotaxis

 

Sphingosine-1-phosphate S1P2 Sphingosine-1-phosphate Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

De novo:
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

ST2 IL-33 Cytokines
TGFb receptor 1 TGFb Decreases IgE dependent degranulation, IgE dependent TNF production
TLR1-9 Bacterial and viral products Cytokines ; dependent upon ligand
Urokinase receptor Urokinase Movement of mast cells
Vitamin D receptor Vitamin D Mast cell development
β2-adrenoreceptor Adrenaline Inhibits FcεRI degranulation and cytokine production and secretion

How to activate mast cells: Receptors and Ligands Master Table (part 2)

Receptor Ligand (molecules that bind to the receptor) Result
Gp49B1 Gp49B1-αvβ3 Inhibits IgE activation
GPCR mimetic MRGX2 Mastoparan, cortistatin, PAMP-12, somatostatin, neuropeptide FF, oxytocin, substance P Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin
GPR34 Lysophosphatidylserine, b defensins, LL-37?? Enhances degranulation:  Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

De novo:

PGD2, PGE2, LTC4, IL-2, IL03, IL-5, IL-1b, TNF, IL-31, GM-CSF, IL-5, TNFg

GPR92 Lysophosphatidic acid Cytokine production and release
Ig-like lectins Inhibitory
IL-10 receptor IL-10 Decreases IgE dependent release of IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5
IL-3 receptor IL-3 Increases IgE dependent release of histamine and leukotriene C4
IL-4 receptor IL-4 Increases IgE dependent release of histamine, leukotriene C4 and IL-5 release
IL-5 receptor IL-5 Increases IgE dependent secretion :
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Leptin receptor Leptin Immunomodulation
Cysteinyl Leukotriene receptor 1, 2 Leukotrienes Cytokine production and proliferation
LPA1, LPA3 Lysophosphatidic acid Encourage development
Mast cell function associated antigen (MAFA) Inhibitory
MHC I Antigenic peptides For activating other immune cells
MHC II Antigenic peptides For activating other immune cells
MRGX2 Mastoparan, somatostatin, substance P, platelet factor 4, mellitin

 

Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

De novo: IL-3, IL-8, TNFa, GM-CSF

Myeloid associated Ig-like receptor 1 Unknown Inhibition of mast cell activation and mediator release
Neurokinin receptors: NK1R, NK2R, NK3R, VPAC2 Substance P, CGRP, hemokinin A, VIP, nerve growth factor, neuropeptide Y Substance P: Degranulation:

Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

Produce and release cytokines

 

VIP, Neuropeptide Y: induce release of histamine

 

CGRP:

Degranulation:

Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

Neurotensin receptor Neurotensin Degranulation
Neurotrophin receptor TrkA NGF Degranulation: histamine, serotonin, NGF
Neurotrophin receptor TrkB BDNF, NT-4 No degranulation
Neurotrophin receptor TrkC Neurotrophin 3 No degranulation

How to activate mast cells: Receptors and ligands Master Table (part 1)

There are many receptors on mast cells.  The molecules that bind to these receptors are called ligands.  Different receptors can cause activation in different ways.

I am posting this table a little at a time as I anticipate getting a lot of questions about it.  I put this together for my own reference and I didn’t keep track of all sources.  I am hoping to go through the literature again and track this at some point.

These tables are not exhaustive, and I’ll add to them over time as I have the chance.

Receptor Ligand (molecules that bind to the receptor) Result
0X40 0X40 ligand Suppression of mast cell activation
A2A, A2B, A3 Adenosine At low concentration, degranulation:

histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

De novo: IL-1b, IL-3, IL-4, IL-8, IL-13

 

At high concentration, inhibits FcεRI degranulation

C3α receptor C3α De novo:
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Increases IgE and IgG dependent degranulation

C5α receptor C5α Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Cannabinoid CB2 receptor 2-arachidonoyl-glycerol, anandamide Suppression of mast cell activity
CCR1 CCL3 (MIP1α), CCL5 (RANTES) Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
CCR3 CCL11 No degranulation
Increases IgE dependent secretion: IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5
CCR4 CCL2 (MCP-1) No degranulation, reléase of cytokines
CCR5 CCL3 (MIP1α), CCL5 (RANTES), CCL4 (MIP1β) No degranulation, reléase of cytokines
CD200 receptor CD200 (OX2) Inhibitory
Cd300α receptor Eosinophilic granule proteins Inhibitory
CD47 (integrin associated protein, IAP) Integrins Histamine secretion
CD48 E. coli, M. tuberculosis Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

De novo : TNFa, IL-6

CD72 CD100 Inhibits CKIT activation
CKIT receptor tyrosine kinase (CD117) Stem cell factor De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Increased IgE dependent degranulation: histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

Corticotropin/ corticotropin releasing hormone receptor CRH, urocortin Secretion of VEGF
CX3CL1 Fractalkine No degranulation
CX3CR1 Chemokines No degranulation, reléase of cytokines
Estrogen receptor Estrogens Increased IgE dependent degranulation: histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
ETA Endothelin-1 Degranulation: Histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin, renin

 

De novo: TNFa, IL-6, VEGF, TGF-b1

ETB Endothelin-1 Unknown
FcαR (CD89) IgA Unknown
FcγRIIA, FcγRI, FcγRIIIA IgG/antigen Degranulation: Histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin, renin

 

De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

FcγRIIIB IgG/antigen Cannot induce activation
FcεRI IgE with or without antigen Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5