Leukotrienes activate the immune system after infection, injury, or contact with allergens. Although their role in inflammatory processes is beneficial to help fight diseases, higher levels of these chemicals can contribute to conditions like asthma, arthritis and allergic reactions. Read on to learn more about leukotrienes and their function.
- What Are Leukotrienes?
- Leukotriene Production
- Functions of Leukotriene B4 (LTB4)
- Functions of Cysteinyl Leukotrienes (CysLT)
- Other Functions of Leukotrienes
- Leukotrienes and Health
- 1) Leukotrienes and Asthma
- 2) Leukotrienes and Allergies
- 3) Leukotrienes and Heart Diseases
- 4) Leukotrienes and Chronic Obstructive Pulmonary Disease (COPD)
- 5) Leukotrienes and Metabolic Disorders
- 6) Leukotrienes and Cancer
- 7) Leukotrienes and Rheumatoid Arthritis
- 8) Leukotrienes and Neurodegenerative Diseases
- 9) Leukotrienes and Stomach Pain
- 10) Leukotrienes and Pain Sensitivity
- 11) Leukotrienes and Lung Tissue Scarring
- How to Lower Leukotriene Levels
- Natural Ways to Block Leukotrienes
- Genetics of Leukotrienes
- Arachidonic Acid Derivatives and Inflammation
What Are Leukotrienes?
Leukotrienes are chemical messengers that powerfully activate the immune response. These molecules are formed from the breakdown of arachidonic acid (AA), a fatty acid component of cell membranes that acts as a precursor for a variety of inflammatory chemicals.
Depending on the enzymes present in the cell, LTA4 is then converted into two main types of leukotrienes:
- Leukotriene B4 (LTB4): This type is formed in immune cells with the enzyme LTA4H (neutrophils and monocytes). Its main function is to promote inflammation by activating the production of inflammatory cells (neutrophils) and molecules (cytokines), and recruiting the cells to specific tissues [R].
- Cysteinyl leukotrienes (CysLT): In immune cells with the enzyme LTC4 synthase (mast cells and eosinophils), LTA4 is transformed into leukotriene C4. Outside the cells, leukotriene C4 is converted to leukotrienes D4 and E4. These types of leukotrienes tighten the airway muscles and produce excess mucus during allergic reactions [R].
In the lipoxygenase pathway (LOX), 5-lipoxygenase (5-LOX) (along with other enzymes) converts arachidonic acid into two types of leukotrienes: leukotriene B4 and cysteinyl leukotrienes (comprising leukotriene C4, D4, and E4) [R, R, R, R].
The 5-Lipoxygenase Pathway [R]
Functions of Leukotriene B4 (LTB4)
Leukotriene B4 has several functions during inflammation and immune defense.
1) Leukotriene B4 Promotes the Migration of White Blood Cells
2) Leukotriene B4 Boosts Antimicrobial Defense
In human white blood cells, leukotriene B4 stimulates the production of molecules with powerful antimicrobial effects (e.g., α-defensins) [R].
Similarly, in a study (DB-RCT) of 23 healthy individuals, spray application of leukotriene B4 in the nose increased the production of myeloperoxidase (MPO) and other antimicrobial proteins after 4 hours [R].
Additionally, in cell-based studies, white blood cells (neutrophils) activated by leukotriene B4 effectively killed several viruses [R].
Leukotriene B4 can also enhance phagocytosis, or the engulfment of bacteria and other disease-causing microorganisms by white blood cells (e.g., macrophages). It does this by binding to its receptor on these cells and activating cellular signals that initiate the process [R, R].
In turn, the activated immune cells attract more cells that produce leukotriene B4, resulting in more activated immune cells [R].
3) Leukotriene B4 Determines the Duration of Inflammatory Responses
PPARα is a protein that promotes the production of enzymes involved in the breakdown of fatty acids and their derivatives, like leukotriene B4. Because leukotriene B4 activates PPARα, its interaction with this protein controls the inflammatory response by reducing its duration [R].
4) Leukotriene B4 Activates the Immune Response
Leukotriene B4 binds to its receptor (BLT1) on dendritic cells (white blood cells that capture and digest foreign substances). This leads to the increased the production of IL-12, which is required for the development of Th1 immunity [R].
Functions of Cysteinyl Leukotrienes (CysLT)
Cysteinyl leukotrienes (leukotrienes C4, D4, and E4) are mostly known for their powerful ability to constrict the airways, increase mucus production, and promote swelling and inflammation in the lungs, which worsens asthma symptoms.
1) Cysteinyl Leukotrienes Recruit White Blood Cells
Inhaling leukotriene E4 increased the number of white blood cells (eosinophils and neutrophils) in the mucus lining of the airways after 4 hours in patients with asthma [R].
In a cell-based study, cytokines IL-4 and IL-13 increased the production of cysteinyl leukotriene receptors (CysLT1) in human monocytes and lung macrophages (white blood cells that capture and “eat” foreign and harmful substances) [R].
2) Cysteinyl Leukotrienes Trigger Cytokine Production
Leukotrienes D4 and E4 trigger the release of IL-4 by eosinophils (white blood cells that fight viral and parasitic infections and cause allergic symptoms). Molecules that block cysteinyl receptors (CysLT1) prevent the production of this cytokine [R, R].
3) Cysteinyl Leukotrienes Are Required for Immune Cell Transport and Function
Leukotrienes C4 and D4 restored the migration of dendritic cells, white blood cells that scavenge foreign substances, in mice lacking a protein that transports leukotriene C4 outside the cell after its synthesis [R, R].
4) Cysteinyl Leukotrienes Promote Blood Vessel Leakiness
In mice deficient in either the enzyme that makes cysteinyl leukotrienes (LTC4S) or receptors for cysteinyl leukotrienes (CysLT1), blood vessel leakage was reduced by 50%. These results indicate the involvement of cysteinyl leukotrienes in increasing blood vessel leakiness [R, R].
Other Functions of Leukotrienes
1) Leukotrienes Enhance the Formation of White Blood Cells
By binding to cysteinyl leukotriene receptors (CysLT1) on blood and bone marrow cells, leukotriene D4 stimulates the formation of eosinophils (white blood cells involved in parasitic and allergic reactions) [R].
In mice, the addition of leukotrienes B4, C4, and D4 to bone marrow cells previously treated with blockers of leukotriene production restored the formation of various types of white blood cells [R].
2) Leukotrienes Promote Bone Loss
Bone mass is maintained by a balance between bone formation and bone loss. During bone loss, cells called osteoclasts break down bone tissue and release its minerals, including calcium, into the blood. In cell-based studies, the addition of leukotrienes B4 and D4 to osteoclasts from birds enhanced the bone loss activity of these cells [R, R].
Additionally, leukotriene B4 promoted the production of functional osteoclasts in human white blood cells [R].
Leukotrienes of all types were also involved in osteoclast recruitment and production during bone loss activity in mice [R].
Leukotrienes and Health
When formed excessively or inappropriately, leukotrienes can be involved in the onset or maintenance of chronic inflammatory diseases.
1) Leukotrienes and Asthma
Asthma patients are very sensitive to breathing in cysteinyl leukotrienes C4, D4, and E4. These molecules narrow the airways, increase mucus production, and promote blood vessel leakiness in the lungs [R].
Leukotriene B4 also worsens asthma symptoms. Although it does not constrict the airways, leukotriene B4 causes fluid buildup and increases mucus secretion, thereby reducing the inner width of the airways [R].
CD8+ T cells play a role in the development of airway constriction and inflammation. A subset of these cells containing the leukotriene B4 receptor (BLT1) has been identified in lung tissue of patients with asthma, indicating an involvement of leukotriene B4 in asthma [R].
Furthermore, in two studies (1 double-blind non-crossover study of 10 patients and 1 double-blind crossover study of 40 patients), a drug (zileuton) that inhibit the enzyme that makes leukotrienes (5-LOX) improved symptoms in patients with asthma [R, R].
2) Leukotrienes and Allergies
In addition, white blood cells from patients with asthma produce more leukotriene B4 and C4 than those from healthy individuals [R].
Patients with chronic sinus infections also respond favorably to drugs that block cysteinyl leukotriene receptors [R].
Both types of leukotrienes are involved in the development of eczema. Leukotriene B4 recruits inflammatory cells to the skin (neutrophils, eosinophils, and Th2 cells), while cysteinyl leukotrienes cause skin scarring [R].
Leukotriene B4 also causes white blood cells to migrate to the mucus lining of the outer eye. This may partly explain why leukotriene B4 levels are higher in the tears of patients with seasonal allergic pink eye [R, R].
The mucus-secreting cells of the rat and human eye contain receptors for cysteinyl leukotrienes. When stimulated by leukotriene D4, these cells secrete mucus, which is carried to the eye surface. This activity may play a role in allergic eye conditions [R].
Treatments for allergic conjunctivitis include:
- The combination of histamine H1 receptor blockers and drugs that block enzymes that make leukotriene B4 [R]
- Leukotriene B4 and cysteinyl leukotriene receptor blockers [R, R].
In anaphylaxis, a life-threatening allergic reaction that occurs after an exposure to an allergen, the increase in blood vessel leakiness is essential, as it enhances the transport of molecules promoting the reaction (leukotrienes, prostaglandins, histamine) [R].
Mice lacking the main receptors for cysteinyl leukotrienes (CysLT1) showed reduced blood vessel leakiness during skin allergic reactions. This response was increased in mice producing high levels of another type of cysteinyl leukotriene receptor (CysLT2) [R, R].
3) Leukotrienes and Heart Diseases
Furthermore, deficiencies in enzymes involved in leukotriene production, as well as treatment with drugs that block these enzymes, prevented artery hardening in mice [R].
The production of all the enzymes involved in the leukotriene pathway is increased in cells located in the arterial walls of patients with hardening of the arteries [R].
In mice fed a high-fat diet, deletion of the enzyme that initiates the production of leukotrienes (5-LOX) protected against an aortic aneurysm (a bulge in the wall of the aorta). However, these effects disappeared under a normal diet [R, R].
The production of cysteinyl leukotrienes is higher in the wall of human stomach aortic aneurysms (enlargements of the stomach aorta). This causes the release of enzymes involved in the development and rupture of aneurysms [R].
In rats, immune cells (macrophages) producing leukotriene B4 damaged blood vessels in the lungs. This effect was prevented by blocking the leukotriene B4 receptor [R].
High levels of cysteinyl leukotrienes were found in newborns with high blood pressure in the lungs. A poor clinical outcome after diagnosis was linked to high levels of leukotrienes B4, C4, and E4 [R, R].
In patients with aortic valve narrowing (stenosis), leukotriene production is activated. Its inflammatory role increases the severity of this disease [R].
4) Leukotrienes and Chronic Obstructive Pulmonary Disease (COPD)
The recruitment of white blood cells to the airways rises during the progression of COPD and declines during its recovery [R].
5) Leukotrienes and Metabolic Disorders
Mice with type 1 diabetes exhibited higher blood leukotriene B4 levels. As a result, their white blood cells (macrophages) produced higher levels of inflammatory cytokines. Treatments with insulin or leukotriene synthesis blockers restored leukotriene B4 levels, thereby reducing inflammation [R].
Furthermore, leukotriene-producing enzyme 5-LOX is activated in both mice with insulin resistance and in fat tissue of obese patients [R].
Its deficiency reduces liver inflammation and liver cell death in mice [R].
Although its products leukotriene B4 and D4 can cause liver cell death, 5-LOX also plays a role in maintaining pancreatic function [R].
6) Leukotrienes and Cancer
In addition, the production of its receptor is higher in human pancreatic tumors [R].
Also, in rats, blocking the enzyme involved in making leukotriene B4 reduces esophageal cancer [R].
7) Leukotrienes and Rheumatoid Arthritis
Leukotriene B4 promotes the stickiness of inflammatory white blood cells (neutrophils) to the walls of blood vessels, which promotes rheumatoid arthritis development by activating the inflammatory response [R].
Additionally, the production of leukotriene B4 receptors is increased in joint tissues and cells from rheumatoid arthritis patients [R].
The severity of this disease is reduced with treatment that blocks these receptors [R].
Deletion of a protein that activates the enzyme responsible for leukotriene production (5-LOX) reduced the severity of rheumatoid arthritis by 73% and its incidence by 23% in mice [R].
Similarly, the presence of functional enzymes that make leukotriene B4 are required for mice to develop the disease [R].
8) Leukotrienes and Neurodegenerative Diseases
Interestingly, Alzheimer’s disease patients show increased production of this enzyme and leukotriene B4 levels compared to healthy individuals [R].
Similarly, in mice brain cells treated with a neurotoxin, the production of an enzyme that initiates leukotriene synthesis (5-LOX) and leukotriene B4 was increased, causing brain cell death. The addition of a blocker of this enzyme promoted the survival of these brain cells [R].
9) Leukotrienes and Stomach Pain
In patients with familial Mediterranean fever (FMF), an inflammatory disorder causing stomach pain, leukotriene B4 urine levels are higher than those of healthy individuals [R].
In 5 children suffering from food allergies, blocking leukotriene receptors with drugs (montelukast sodium) prevented stomach pain during a year of oral immunotherapy [R].
Conversely, stomach pain was the most common non-psychiatric side effect observed in children with asthma or early wheezing treated with leukotriene receptor blockers [R].
10) Leukotrienes and Pain Sensitivity
After nerve injury, levels of leukotriene B4 and its receptor (BLT1) are higher in spinal nerve cells. This enhances the activity of receptors involved in pain (NMDA), ultimately increasing pain sensitivity [R].
Similarly, leukotriene B4 binding to its receptor enhances the activity of receptors involved in inflammatory pain, TRPV1. While low concentrations of this leukotriene trigger this process, higher concentrations allow leukotriene B4 to bind with another receptor (BLT2), leading to an opposite effect [R].
11) Leukotrienes and Lung Tissue Scarring
How to Lower Leukotriene Levels
The most useful strategy to decrease leukotriene production is to reduce the activity of:
- Phospholipase A2 (cPLA2 ), the enzyme that releases arachidonic acid from the cell membrane [R]
- 5-lipoxygenase (5-LOX), the enzyme that initiates the leukotriene pathway [R]
- FLAP, the activating protein of 5-lipoxygenase [R]
5-LOX inhibitors include:
- Phenidone and BW755C [R]
- Iron chelating agents such as BWA4C or zileuton, the only one on the market [R]
- ZM230487, CJ-13610, or PF-4191834 [R]
- Indirubin and hyperforin [R, R]
In the recent years, the following compounds blocking 5-LOX have been tested with promising results:
FLAP blockers include:
These compounds lose effectiveness in conditions when arachidonic acid and its derivatives are too high.
New FLAP inhibitors with promising results in clinical studies include:
In this respect, blocking LTA4H and LTC4S is more preferable.
The first LTA4H inhibitors were:
These drugs had low effectiveness and were not selective. New and promising LTA4H inhibitors include:
LTC4S inhibitors are rare and inefficient, as is the case for:
- Helenalin [R]
- Thymoquinone [R]
- The FLAP inhibitor MK886, which can also inhibit LTC4S (although to a lower degree) based on the genetic similarity between both proteins [R]
Leukotriene Receptor Antagonists
Leukotriene receptor antagonists (also known as leukotriene modifiers) are drugs that block the action of leukotrienes by preventing their binding to their receptors. The main leukotriene B4 antagonists tested in clinical trials are:
- Etalocib (LY293111) blocks the leukotriene B4 (BLT1) receptor and deactivates 5-LOX. In a cell-based study, it caused cell death in pancreatic cancer cells. However, it failed to increase the progression-free survival of patients in a study (DB-RCT) of 195 patients with lung cancer [R, R].
- CP-105696 is a very powerful leukotriene B4 receptor (BLT1) blocker. It successfully reduced the progression of artery hardening in a mouse preclinical model [R, R].
- The leukotriene B4 receptor (BLT1) blocker Amelubant (BIIL284) reduces artery hardening in mice. However, in a phase II trial (DB-RCT) with 420 patients, this drug increased the incidence of serious side effects in patients using it as cystic tissue scarring treatment [R, R].
- Moxilubant (CGS-25019C) is a powerful blocker of the leukotriene B4 receptor (BLT1). In mice, it reduced leukotriene B4-induced ear liquid buildup and low white blood cell levels. However, its performance in a phase II trial with 24 COPD patients was poor [R R].
- RO5101576 prevented leukotriene B4-induced lung inflammatory responses in guinea pigs and monkeys, as well as blocking human white blood cell movement [R]
The most widely used leukotriene receptor blockers are those preventing cysteinyl leukotrienes from binding to their receptor, CysLT1. The main commercial drugs in this category are montelukast, zafirlukast, and pranlukast.
Montelukast can be used to treat the symptoms of:
- Allergic rhinitis. Its effects are enhanced by antihistamines [R, R]
- Moderate asthma in adults (including smokers), elderly patients, and children [R, R, R, R]
- Aspirin-, exercise- and allergen-induced asthma [R, R, R]
- Chronic obstructive pulmonary disease (COPD) [R, R]
- Improves nasal airflow in patients with allergic rhinitis and reduces nose stuffiness in those allergic to cats [R, R].
- Reduces excessive airway tightening caused by exercise and moderate asthma in long-term trials [R, R, R]
- Reduces inflammation in patients with allergic asthma by reducing the influx of white blood cells into the airways and decreasing macrophage (immune cells that capture and digest foreign and harmful material) activation [R]
- Improves lung function by widening the airways in patients with chronic obstructive pulmonary disease (COPD), especially in smokers [R, R]
Pranlukast is used to treat:
- Moderate and severe asthma in patients who are not being treated with oral steroids [R, R]
- Airway inflammation in patients treated with oral corticosteroids [R]
Natural Ways to Block Leukotrienes
These plant compounds (alkaloids) blocked the formation of leukotrienes and prostaglandins in cell-based studies:
- Berbamine (found in barberries) [R]
- Tetrandrine (found in the Chinese medical herb Stephania tetrandra) [R]
These plant pigments (flavonoids) blocked 5-lipoxygenase (5-LOX), the enzyme that initiates the leukotriene pathway, in cell-based studies:
- Velutin (found in the pink banana) [R]
- Galangin (found in honey and the herb lesser galangal) [R]
- Chrysin (found in honey, propolis, honeycomb, passion flowers and Oroxylum indicum) [R]
Artonin E (a compound from the root bark of Artocarpus elasticus) effectively blocked 5-LOX purified from pig white cells [R].
Caffeic acid phenyl ester (CAPE), the active component of honeybee propolis extract, blocks 5-LOX activity and the release of arachidonic acid. In rats, it reduced the production of leukotrienes after stroke [R, R].
In a cell-based study, capsaicin (found in peppers) and curcumin reduced the conversion of arachidonic into leukotrienes B4 (capsaicin by 46%; curcumin by 61%) and C4 (capsaicin, 48%; curcumin, 34%) in rat macrophages [R].
A compound in double palm (dammarane triterpenoid 1) triggered cell death in pancreatic and prostate cancer cells in part by inhibiting 5-LOX [R].
The root of Dystaenia takeshimana contains numerous compounds that inhibited 5-LOX in cell-based studies, namely the coumarins:
and the flavonoids:
A component of Rutaceae, goshuyuamide II, inhibits 5-LOX, resulting in reduced leukotriene B4 production [R].
Diets high in fish oil fatty acids (EPA; mainly found in salmon, sturgeon, eels, oysters, lobsters, shrimps, and crabs and DHA; mainly found in sardines, salmon, trout, tuna, and shellfish) may have anti-inflammatory effects by inhibiting 5-LOX in white blood cells (neutrophils and monocytes) [R].
Garcinol (found in kokum -Garcinia indica-) has anti-cancer effects by blocking leukotriene B4 production [R].
- Epigallocatechin-3-gallate (EGCG)
- Epigallocatechin (EGC)
- Epicatechin-3-gallate (ECG)
The following compounds from American witch hazel potently inhibited 5-LOX in cell-based studies:
Huang-Lian-Jie-Du-Tang (HLJDT), a traditional Chinese prescription with anti-inflammatory properties, contains the extracts of:
- Baical skullcap (Scutellaria baicalensis): Its compounds baicalein and baicalin powerfully block 5-LOX [R]
- Coptis Root (Rhizoma coptidis): Its compound coptisine shows moderate blocking of the enzyme that makes leukotriene B4 (LTA4H) [R].
In rats, lycopene (found in tomatoes, guava, watermelon, sweet red peppers, grapefruit asparagus, and purple cabbage among others) blocked the production of 5-LOX in macrophages found in the thin layer of tissue that lines the stomach and the prostate [R].
The plant hormone methyl jasmonate triggered cell death in human prostate cancer cells by inhibiting 5-LOX [R].
Pygeum africanum extract inhibits the byproducts of the 5-LOX enzyme [R].
Other compounds acting as potent inhibitors of 5-LOX include:
- Kaempferol (found in apples, grapes, tomatoes, green tea, potatoes, onion, and broccoli among others) [R]
- Morin (found in Osage orange, old fustic, and common guava) [R]
- Myricetin (found in Japanese raisin tree and vine tea extracts, parsley, cranberries, broad beans, and blueberries) [R].
Resveratrol also blocks pancreatic cancer by inhibiting the enzyme that makes leukotriene B4 (LTA4H) [R].
Stemona species’ alkaloids block leukotriene formation:
- Pinosylvin [R]
- Dihydropinosylvin [R]
- Stilbostemin A, B, D, F, and G [R]
- Stemofuran B, C, D, G, and J [R]
- Stemanthrene A, B, C, and D [R]
Triptolide (found in the Chinese herb thunder god vine -Tripterygium wilfordii-) exerts its anti-pancreatic cancer activity by blocking the leukotriene pathway [R].
Genetics of Leukotrienes
Genetic variants in FLAP (the activating protein of 5-LOX, the enzyme that initiates the lipoxygenase pathway) (rs17222814) and LTA4H (enzyme that makes leukotriene B4) (rs2247570) are linked to an increased risk of heart attack [R, R].
Genetic mutations that affect the production of the enzyme that initiates leukotriene synthesis (5-LOX) also increase the risk of artery hardening. This effect can be promoted by dietary omega-6 fatty acids and inhibited by omega-3 fatty acids [R].
Arachidonic Acid Derivatives and Inflammation
The Cyclooxygenase Pathway [R]
Prostaglandin D2 (PGD2) is produced following exposure to allergens. Its main functions include:
- Smooth muscle contraction [R]
- Widening of blood vessels [R]
- Enhanced responses to histamine [R]
- Promotions of the migration and activation of white blood cells [R, R, R]
Prostaglandin E2 (PGE2):
- Causes the main inflammatory symptoms (redness, swelling and pain) [R]
- Generates fever [R]
- Accelerates wound healing [R]
- Maintains blood vessel tone [R]
- Promotes the migration and maturation of Th17 white blood cell [R]
- Suppresses the production of inflammatory molecules (cytokines) [R, R]
Prostaglandin F2α (PGF2α):
- Constricts blood vessel and bronchial smooth muscle. It is involved in short-term and chronic inflammation. High levels of this prostaglandin are found in patients with arthritis [R, R, R, R]
Prostaglandin I2 (PGI2):
- Widens blood vessels [R]
- Causes fluid buildup and pain in inflamed tissues [R]
- Accelerates wound healing in the blood vessels [R]
- Promotes inflammation in some conditions (rheumatoid arthritis) while reducing it in others (lung vessel diseases, artery hardening) [R]
Thromboxane A2 (TXA2):
- Promotes the clumping together of platelets [R, R]
- Causes smooth muscle contraction [R, R]
- Activates inflammatory responses [R, R]
Interaction between Leukotrienes and Prostaglandins
Leukotrienes can interact with prostaglandins in many ways during inflammation or injury. They can either block each others production and effects or enhance them.
Antagonistic (opposing) interactions:
- Prostaglandin E2 blocks the release of cysteinyl leukotrienes from white blood cells [R, R]
- Prostaglandins E1 and E2 inhibit the production of leukotriene B4 [R]
- Leukotrienes and prostaglandin E2 have opposing effects in promoting and preventing phagocytosis (cell engulfing) by white blood cells [R]
Synergistic (working together) interactions:
- Leukotriene E4 increases the production of prostaglandin D2 [R]
- Prostaglandin D2 enhances leukotriene C4 production [R]
- The combination of leukotriene E4 and prostaglandin D2 enhances Th2 cytokine production [R, R]
- Leukotriene D4 and prostaglandin E2 increase blood vessel inflammation and prostaglandin D2 production by mast cells [R]
- Combination of cysteinyl leukotrienes and TXA2 in the nose increase nose stuffiness [R]
Leukotriene E4 enhances the effects prostaglandin D2 in activating cytokine production by a type of white blood cells (ILC2s) in patients with asthma [R]
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