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Leukotrienes: Function & Associated Diseases

Written by Carlos Tello, PhD (Molecular Biology) | Last updated:
Medically reviewed by
Evguenia Alechine, PhD (Biochemistry), Puya Yazdi, MD | Written by Carlos Tello, PhD (Molecular Biology) | Last updated:

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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?

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.

More specifically, the enzyme 5-lipoxygenase (5-LOX) converts arachidonic acid into leukotriene A4 (LTA4) in white blood cells.

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 [1].
  • 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 [1].

Leukotriene Production

During inflammation or tissue injury, arachidonic acid is released from the cell membranes by the enzyme cPLA2 [2, 3].

The free arachidonic acid can then be broken down for the production of leukotrienes or prostaglandins [4, 5].


Arachidonic acid pathway

Source: [6]

Lipoxygenase Pathway

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) [7, 8, 9, 10].


Lipoxygenase pathway


The 5-Lipoxygenase Pathway [11]

Functions of Leukotriene B4 (LTB4)

Leukotriene B4 has several functions during inflammation and immune defense.

1) Promotes the Migration of White Blood Cells

Leukotriene B4 recruits white blood cells (neutrophils, CD4+ T cells, and CD8+ T cells) to sites of inflammation and injury by binding to its receptor (BLT1) on these cells [12, 13, 14, 15].

In response to infections and allergic reactions, immune cells (mast cells) release leukotrienes, which attract white blood cells (neutrophils and CD8+ T cells) to the affected areas [16, 17, 18].

2) Boosts Antimicrobial Defense

In human white blood cells, leukotriene B4 stimulates the production of molecules with powerful antimicrobial effects (e.g., α-defensins) [19].

Aside from clearing away bacteria and viruses, these molecules also increase the production of leukotriene B4 [20, 21].

In mice infected with influenza A virus, leukotriene B4 significantly reduced the amount of the virus in the lung by stimulating the release of antimicrobial proteins [22].

Similarly, in a clinical trial on 23 healthy people, spray application of leukotriene B4 in the nose increased the production of myeloperoxidase (MPO) and other antimicrobial proteins after 4 hours [23].

Additionally, in cell-based studies, white blood cells (neutrophils) activated by leukotriene B4 effectively killed several viruses [23].

However, in another clinical trial study in 18 healthy people infected with the virus HRV-16, leukotriene B4 failed to reduce the incidence of common cold and its symptoms after 6 days [23].

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 [24, 25].

In turn, the activated immune cells attract more cells that produce leukotriene B4, resulting in more activated immune cells [24].

Leukotriene B4 also suppresses the action of another fat messenger (PGE2) in blocking phagocytosis [26].

3) 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 [27].

4) 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 production of IL-12, which is required for the development of Th1 immunity [28].

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) Recruit White Blood Cells

Inhaling leukotriene E4 increased the number of white blood cells (eosinophils and neutrophils) in the mucous lining of the airways after 4 hours in patients with asthma [29].

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) [30].

Receptors for cysteinyl leukotrienes are also highly concentrated in white blood cells (eosinophils and mast cells) from nose tissues of patients with hay fever and nose inflammation [31, 32].

Similarly, the production of cysteinyl leukotriene receptors (CysLT1) is increased in white blood cells from people with aspirin-sensitive chronic nose inflammation (rhinosinusitis) [32].

2) 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 [33, 34].

Mast cells (white blood cells involved in allergic reactions) also release various cytokines including IL-5 and TNF-α in response to leukotriene C4 and E4 stimulation [35, 36].

3) 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 [37, 38].

In asthmatic mice, cysteinyl leukotrienes triggered a Th2 response in the lungs by increasing IL-5 production from dendritic cells [39].

4) 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 [40, 41].

Other Functions of Leukotrienes

1) 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) [42].

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 [43].

Cysteinyl leukotrienes can also override the inhibition of white blood cell (eosinophil) production by other inflammatory molecules (prostaglandin E2) [44].

2) 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 [45, 46].

Additionally, leukotriene B4 promoted the production of functional osteoclasts in human white blood cells [47].

Leukotrienes of all types were also involved in osteoclast recruitment and production during bone loss activity in mice [48].

Leukotrienes and Health

When formed excessively or inappropriately, leukotrienes can be involved in the onset or maintenance of chronic inflammatory diseases.

1) Asthma

People with asthma 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 [49].

In addition, they recruit inflammatory cells (eosinophils) that are involved in the development of asthma into the mucus lining of the airways [50, 51, 52, 53].

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 [54].

It is found in high concentration in the breath samples of patients with severe and chronic asthma [55, 56].

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 [57].

Furthermore, in two clinical trials on 50 people, a drug (zileuton) that inhibits the enzyme that makes leukotrienes (5-LOX) improved symptoms in those with asthma [58, 59].

2) Allergies

People with hay fever (allergic rhinitis) show increased levels of all types of leukotrienes in their nose and breath [60, 61].

In addition, white blood cells from patients with asthma produce more leukotriene B4 and C4 than those from healthy individuals [62].

Furthermore, drugs that inhibit the enzyme that makes leukotrienes (5-LOX) in people with seasonal allergies reduced symptoms and leukotriene B4 levels [63, 64].

People with chronic sinus infections also respond favorably to drugs that block cysteinyl leukotriene receptors [65].

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 [66].

Additionally, high levels of leukotriene B4 and C4 are found in skin lesions of people with eczema [67, 68].

In mice with eczema, scratching triggers allergic skin inflammation, which is mediated by leukotriene B4 binding to its receptor [69].

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 [70, 71].

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 [72].

Treatments for allergic conjunctivitis include:

  • The combination of histamine H1 receptor blockers and drugs that block enzymes that make leukotriene B4 [73]
  • Leukotriene B4 and cysteinyl leukotriene receptor blockers [74, 75].

In anaphylaxis, a life-threatening allergic reaction that occurs after 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) [76].

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) [41, 77].

3) Heart Disease

Leukotriene B4 is produced in plaques (build-up of cholesterol, fat, and calcium) inside the arteries [78].

In addition, patients with heart disease have higher levels of leukotriene E4 in the urine [79].

Furthermore, deficiencies in enzymes involved in leukotriene production, as well as treatment with drugs that block these enzymes, prevented artery hardening in mice [80].

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 [81].

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 [82, 83].

Both the deletion of the leukotriene B4 receptor (BLT1) and treatment with a drug that blocks this receptor prevented the early development of an aneurysm in mice [84, 85].

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 [86].

Similarly, elevated levels of cysteinyl leukotrienes have been observed in both mice and human patients after brain ischemia [87, 88].

In rats, immune cells (macrophages) producing leukotriene B4 damaged blood vessels in the lungs. This effect was prevented by blocking the leukotriene B4 receptor [89].

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 [90, 91].

Leukotriene production is activated in people with aortic valve narrowing (stenosis). Its inflammatory role increases the severity of this disease [92].

4) Chronic Obstructive Pulmonary Disease (COPD)

Leukotriene B4 is higher in the exhaled breath samples of patients with COPD than in those of healthy people [93].

The recruitment of white blood cells to the airways rises during the progression of COPD and declines during its recovery [94].

5) 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 [95].

Leukotriene B4 levels are elevated in fat tissue, where they trigger the production of cytokines and worsen inflammation [96, 97, 98].

The binding of leukotriene B4 to its receptor promotes insulin resistance in obese mice [99].

Furthermore, the leukotriene-producing enzyme 5-LOX is activated in both mice with insulin resistance and in fat tissue of obese patients [100].

Its deficiency reduces liver inflammation and liver cell death in mice [101].

Although its products leukotriene B4 and D4 can cause liver cell death, 5-LOX also plays a role in maintaining pancreatic function [102].

6) Cancer

Leukotriene B4 levels are increased in human colon and prostate cancer tissues [103, 104].

In addition, the production of its receptor is higher in human pancreatic tumors [105].

Also, in rats, blocking the enzyme involved in making leukotriene B4 reduces esophageal cancer [106].

In cell-based studies, high levels of leukotriene D4 led to an increased production of colon COX2, which promotes colon cancer [107].

Cysteinyl leukotriene receptors (CysLT1) are also very abundant in human colon and prostate cancer. Higher concentrations are linked to poor survival [108, 109].

Additionally, leukotrienes of both types enhance the survival, stickiness, and migration of colon cancer cells [110, 111].

However, cysteinyl leukotrienes have opposing effects in colorectal cancer. Depending on which receptor they bind to, they can promote (CysLT1) or reduce (CysLT2) cancer cell reproduction [112].

7) Rheumatoid Arthritis

Leukotriene B4 causes inflammatory white blood cells (neutrophils) to stick to the walls of blood vessels, which promotes rheumatoid arthritis development by activating the inflammatory response [113].

Additionally, the production of leukotriene B4 receptors is increased in joint tissues and cells from people with rheumatoid arthritis [114].

The severity of this disease is reduced with treatments that blocks these receptors [115].

The 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 [116].

Similarly, the presence of functional enzymes that make leukotriene B4 are required for mice to develop the disease [117].

8) Neurodegenerative Diseases

By activating the inflammatory NF-kB pathway, leukotriene D4 increases enzymes that produce amyloid-β, ultimately increasing the risk of Alzheimer’s disease [118].

Eliminating the enzyme required for leukotriene production (5-LOX) slows the progression of Alzheimer’s in mice [119, 120].

Interestingly, people with Alzheimer’s disease show increased production of this enzyme and leukotriene B4 levels compared to healthy individuals [121].

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 [122].

9) Stomach Pain

In people with familial Mediterranean fever (FMF), an inflammatory disorder causing stomach pain, leukotriene B4 levels in urine are higher than those of healthy people [123].

Additionally, high concentrations of leukotrienes B4, C4, and D4 are found in the stomach juices of children infected with Helicobacter pylori, thus causing stomach pain [124].

In 5 children suffering from food allergies, blocking leukotriene receptors with drugs (montelukast sodium) prevented stomach pain during a year of oral immunotherapy [125].

This strategy also relieved symptoms of stomach pain in other inflammatory diseases like Henoch-Schönlein purpura, mastocytosis, and eosinophilic gastroenteritis [126, 127, 128].

Conversely, stomach pain was the most common non-psychiatric side effect observed in children with asthma or early wheezing treated with leukotriene receptor blockers [129].

10) Pain Sensitivity

After nerve injury, the 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 [130].

Similarly, leukotriene B4 binding to its receptor enhances the activity of a receptor involved in inflammatory pain (TRPV1). While low concentrations of this leukotriene trigger this process, higher concentrations allow leukotriene B4 to bind to another receptor (BLT2), leading to an opposite effect [131].

11) Lung Tissue Scarring

In mice lacking the necessary agents for leukotriene production, chronic lung inflammation and tissue scarring were reduced [132, 133, 134].

How to Lower Leukotriene Levels

Leukotriene Inhibitors

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 [135]
  • 5-lipoxygenase (5-LOX), the enzyme that initiates the leukotriene pathway [135]
  • FLAP, the activating protein of 5-lipoxygenase [135]

In contrast, the inhibition of LTA4H only reduces leukotriene B4 formation while that of LTC4S (enzyme that makes cysteinyl leukotrienes) only blocks cysteinyl leukotriene production [135].

5-LOX inhibitors include:

The main disadvantage of 5-LOX and FLAP inhibitors is the impaired production of anti-inflammatory compounds (lipoxins and resolvins) [138].

In this respect, blocking LTA4H and LTC4S is preferable.

The first LTA4H inhibitors were:

LTC4S inhibitors are rare and inefficient, as is the case for:

  • Helenalin [141]
  • Thymoquinone [142]

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): it blocks 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 progression-free survival in a clinical trial on almost 200 people with lung cancer [143, 144].
  • CP-105696: this powerful leukotriene B4 receptor (BLT1) blocker successfully reduced the progression of artery hardening in mice [145, 146].
  • Amelubant (BIIL284): this leukotriene B4 receptor (BLT1) blocker reduced artery hardening in mice. However, in a clinical trial on over 400 people, this drug increased the incidence of serious side effects in those using it as cystic tissue scarring treatment [147, 148].
  • Moxilubant (CGS-25019C): it 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 clinical trial on 24 people with COPD was poor [149 150].
  • RO5101576: it prevented leukotriene B4-induced lung inflammatory responses in guinea pigs and monkeys, as well as blocking human white blood cell movement [151].

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 [53, 152]
  • Moderate asthma in adults (including smokers), elderly patients, and children [153, 154, 155, 156]
  • Aspirin-, exercise- and allergen-induced asthma [157, 158, 159]
  • Chronic obstructive pulmonary disease (COPD) [160, 161]


  • Improves nasal airflow in people with allergic rhinitis and reduces nose stuffiness in those allergic to cats [162, 163].
  • Reduces excessive airway tightening caused by exercise and moderate asthma in long-term trials [164, 165, 166]
  • Reduces inflammation in people 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 [167]
  • Improves lung function by widening the airways in people with chronic obstructive pulmonary disease (COPD), especially in smokers [168, 169]

Pranlukast is used to treat:

  • Moderate and severe asthma in people who are not being treated with oral steroids [170, 171]
  • Airway inflammation in people treated with oral corticosteroids [172]

Natural Ways to Block Leukotrienes

Some natural substances have been found to reduce leukotriene production in animals and cells. However, whether they may help with inflammatory conditions triggered by these molecules in humans remains unknown. If you want to use these compounds as a supportive measure, talk to your doctor to avoid any unexpected interactions.

These plant compounds (alkaloids) blocked the formation of leukotrienes and prostaglandins in cell-based studies:

  • Berbamine (found in barberries) [173]
  • Tetrandrine (found in the Chinese medical herb Stephania tetrandra) [173]

These plant pigments (flavonoids) blocked 5-lipoxygenase (5-LOX), the enzyme that initiates the leukotriene pathway, in cell-based studies:

Aloe vera’s component, alprogen, prevented the formation of mast cells (white blood cells that participate in allergic reactions) in guinea pigs, thereby preventing leukotriene release [175].

Artonin E (a compound from the root bark of Artocarpus elasticus) effectively blocked 5-LOX purified from pig white cells [176].

Boswellia (found in frankincense) blocks leukotriene production. Therefore, it can reduce and prevent inflammation in many chronic inflammatory diseases like asthma [177].

Butterbur compounds (isopetasin and oxopetasan esters) prevented the production of leukotrienes in cell-based studies [178].

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 [179, 180].

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 [181].

Curcumin inhibited 5-LOX in rat white blood cells, which prevented the production of leukotrienes. In mice, this compound inhibited the formation of leukotriene C4 and PGD2 [182, 183, 184].

A compound in double palm (dammarane triterpenoid 1) triggered cell death in pancreatic and prostate cancer cells in part by inhibiting 5-LOX [185].

The root of Dystaenia takeshimana contains numerous compounds that inhibited 5-LOX in cell-based studies, namely the coumarins:

  • Psoralen [186]
  • Xanthotoxin [186]
  • Scopoletin [186]
  • Umbelliferone [186]
  • Marmesin [186]

and the flavonoids:

A component of fruits from the citrus family (Rutaceae), goshuyuamide II, inhibits leukotriene B4 production by inhibiting 5-LOX [187].

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) [188].

Garcinol (found in kokum -Garcinia indica-) blocks leukotriene B4 production [189].

Ginger blocks the production of prostaglandins and leukotrienes [190].

Green and black tea contain the following compounds that inhibit various lipoxygenase enzymes (5-, 12- and 15-LOX) [191] :

  • Epigallocatechin-3-gallate (EGCG)
  • Epigallocatechin (EGC)
  • Epicatechin-3-gallate (ECG)

Theaflavins found in black tea leaves blocked leukotriene production in animal studies [192].

The following compounds from American witch hazel potently inhibited 5-LOX in cell-based studies:

  • Hamamelitanin [193]
  • Galloylated proanthocyanidins [193]

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 [194]
  • Coptis Root (Rhizoma coptidis): Its compound coptisine shows moderate blocking of the enzyme that makes leukotriene B4 (LTA4H) [195].

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 [196].

The plant hormone methyl jasmonate triggered cell death in human prostate cancer cells by inhibiting 5-LOX [197].

In rat white blood cells, treatment with plant-derived oleanolic acid inhibited leukotriene B4 production [198].

This fatty acid, together with ursolic acid, contributes to the anti-inflammatory activity of the medicinal plant Helichrysum picardii in part by inhibiting 5-LOX [199].

Pygeum africanum extract inhibits the byproducts of the 5-LOX enzyme [200].

Quercetin (found in capers, red onion, radicchio, kale, buckwheat, dill, and cilantro among others) reduces the release of histamine, leukotrienes, and prostaglandins [201].

Other compounds acting as potent inhibitors of 5-LOX include:

  • Kaempferol (found in apples, grapes, tomatoes, green tea, potatoes, onion, and broccoli among others) [202]
  • Morin (found in Osage orange, old fustic, and common guava) [202]
  • Myricetin (found in Japanese raisin tree and vine tea extracts, parsley, cranberries, broad beans, and blueberries) [202].

Resveratrol (found in the skin of grapes, blueberries, raspberries, and mulberries) acts as a competitive inhibitor of 5-LOX [203].

Stemona species’ alkaloids block leukotriene formation:

  • Pinosylvin [205]
  • Dihydropinosylvin [205]
  • Stilbostemin A, B, D, F, and G [205]
  • Stemofuran B, C, D, G, and J [205]
  • Stemanthrene A, B, C, and D [205]

Thymoquinone (found in black cumin seed) showed 5-LOX and LTC4S (enzyme that makes cysteinyl leukotrienes)-inhibitory activity in human blood cells [142].

Triptolide (found in the Chinese herb thunder god vine -Tripterygium wilfordii-) exerts its anti-pancreatic cancer activity by blocking the leukotriene pathway [206].

Genetics of Leukotrienes

Genetic variants in FLAP (the activating protein of 5-LOX, the enzyme that initiates the lipoxygenase pathway) (rs17222814) and LTA4H (an enzyme that makes leukotriene B4) (rs2247570) are linked to an increased risk of heart attack [207, 208].

Genetic variants 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 [209].

The A allele of a FLAP variant (rs4769874) increases the risk of Alzheimer’s disease 1.41 fold [210].

Arachidonic Acid Derivatives and Inflammation

Cyclooxygenase Pathway

In the cyclooxygenase pathway, cyclooxygenases (COX1 and COX2) and other enzymes convert arachidonic acid into different types of prostaglandins [211, 212, 213].

The Cyclooxygenase Pathway [214]

Prostaglandin D2 (PGD2) is produced following exposure to allergens. Its main functions include:

  • Smooth muscle contraction [215]
  • Widening of blood vessels [216]
  • Enhanced responses to histamine [217]
  • Promotion of the migration and activation of white blood cells [218, 219, 220]

Prostaglandin E2 (PGE2):

  • Causes the main inflammatory symptoms (redness, swelling, and pain) [221]
  • Generates fever [222]
  • Accelerates wound healing [223]
  • Maintains blood vessel tone [224]
  • Promotes the migration and maturation of Th17 white blood cell [225]
  • Suppresses the production of inflammatory molecules (cytokines) [226, 227]

Prostaglandin F2α (PGF2α):

  • Tightens the smooth muscles of the blood vessels and bronchi. It is involved in short-term and chronic inflammation. People with arthritis have high levels of this prostaglandin [228, 229, 230, 231]

Prostaglandin I2 (PGI2):

  • Widens blood vessels [232]
  • Causes fluid buildup and pain in inflamed tissues [233]
  • Accelerates wound healing in the blood vessels [234]
  • Promotes inflammation in some conditions (rheumatoid arthritis) while reducing it in others (lung vessel diseases, artery hardening) [235]

Thromboxane A2 (TXA2):

  • Promotes the clumping together of platelets [236, 237]
  • Causes smooth muscle contraction [236, 237]
  • Activates inflammatory responses [236, 237]

Interaction between Leukotrienes and Prostaglandins

Leukotrienes can interact with prostaglandins in many ways during inflammation or injury. They can either block each other’s production and effects or enhance them.

Antagonistic (opposing) interactions:

  • Prostaglandin E2 blocks the release of cysteinyl leukotrienes from white blood cells [238, 239].
  • Prostaglandins E1 and E2 inhibit the production of leukotriene B4 [240].
  • Leukotrienes and prostaglandin E2 have opposing effects in promoting and preventing phagocytosis (cell engulfing) by white blood cells [26].

Synergistic (working together) interactions:

  • Leukotriene E4 increases the production of prostaglandin D2 [241].
  • Prostaglandin D2 enhances leukotriene C4 production [242].
  • The combination of leukotriene E4 and prostaglandin D2 enhances Th2 cytokine production [243, 244].
  • Leukotriene D4 and prostaglandin E2 increase blood vessel inflammation and prostaglandin D2 production by mast cells [245].
  • The combination of cysteinyl leukotrienes and TXA2 in the nose increase nose stuffiness [246].

Leukotriene E4 enhances the effects of prostaglandin D2 in activating cytokine production by a type of white blood cells (ILC2s) in people with asthma [247].

Want More Targeted Ways to Combat Inflammation?

If you’re interested in natural and targeted ways of lowering your inflammation, we recommend checking out SelfDecode’s Inflammation DNA Wellness Report. It gives genetic-based diet, lifestyle and supplement tips that can help reduce inflammation levels. The recommendations are personalized based on your genes.

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About the Author

Carlos Tello

PhD (Molecular Biology)
Carlos received his PhD and MS from the Universidad de Sevilla.
Carlos spent 9 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and non-academic audiences. He strongly believes that scientific literacy is crucial to maintain a healthy lifestyle and avoid falling for scams.

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