Prostaglandins are released whenever cells are damaged, stressed, or stimulated by specific chemical signals. The process starts when an enzyme called phospholipase A2 clips a fatty acid from the outer membrane of a cell, freeing it to be converted into prostaglandins by a second set of enzymes. This happens throughout the body, but the triggers and the types of prostaglandins produced vary depending on the tissue and the situation.
How Cells Make Prostaglandins
Every cell membrane contains a fatty acid called arachidonic acid embedded in its outer layer. Under normal conditions, it stays locked in place. When a cell receives the right signal, phospholipase A2 breaks arachidonic acid free. From there, enzymes called cyclooxygenases (COX) convert it first into intermediate compounds, then into specific prostaglandins tailored to the tissue where they’re made.
There are two main versions of the COX enzyme. COX-1 runs constantly in many tissues, producing low levels of prostaglandins that handle routine maintenance: protecting the stomach lining, supporting kidney blood flow, and helping platelets function. COX-2 is different. It’s normally quiet but ramps up dramatically in response to injury, infection, or inflammation. This distinction matters because it explains why anti-inflammatory drugs like ibuprofen work the way they do, and why they cause side effects.
In the brain, there’s actually an alternative pathway. Rather than relying on phospholipase A2, brain cells can generate arachidonic acid by breaking down an endocannabinoid compound called 2-AG. This route turns out to be a major source of prostaglandins during fever and neuroinflammation.
Tissue Damage and Inflammation
Physical injury is one of the most powerful triggers for prostaglandin release. When cells are crushed, torn, or burned, their membranes rupture and release arachidonic acid directly. Nearby cells that survive the initial damage ramp up COX-2 production in response to inflammatory signals from immune cells. COX-2 is considered the rate-limiting step in this process: the more COX-2 a cell produces, the more prostaglandins it makes.
The immune system amplifies the response. White blood cells arriving at a wound or infection site release cytokines, particularly interleukin-1, which push surrounding cells to produce even more COX-2 and, consequently, more prostaglandins. Bacterial toxins called lipopolysaccharides do the same thing. This is why infections often produce the same swelling, redness, and pain as a physical wound. The prostaglandins generated through this cascade sensitize nerve endings to pain, dilate blood vessels to increase blood flow, and raise the temperature of inflamed tissue.
Fever
When you’re sick, prostaglandin E2 is the molecule that actually resets your body’s thermostat. Immune cells detecting an infection release cytokines like interleukin-1 into the bloodstream. These reach the brain, where they trigger prostaglandin E2 production in and around the hypothalamus, the region that controls body temperature. The prostaglandin E2 then acts on specific receptors on hypothalamic neurons, raising the temperature set point and producing fever.
Interestingly, the brain appears to rely heavily on the endocannabinoid pathway rather than the standard phospholipase route to generate the arachidonic acid needed for fever. When researchers blocked the enzyme that breaks down 2-AG in mice, fever responses to both bacterial toxins and interleukin-1 dropped significantly. Blocking phospholipase A2, on the other hand, didn’t prevent fever. This helps explain why fever has proven difficult to fully suppress with drugs that target only one arm of the prostaglandin production system.
Menstruation and Uterine Contractions
The uterine lining is one of the most active prostaglandin-producing tissues in the body, and the amounts it generates shift dramatically across the menstrual cycle. During the first half of the cycle, prostaglandin levels in the endometrium are low, around 10 to 25 nanograms per 100 milligrams of tissue for both prostaglandin F2α and E2.
As the cycle progresses into the luteal phase, prostaglandin F2α rises sharply to 65 to 75 nanograms per 100 milligrams. Prostaglandin E2 peaks at menstruation itself, reaching about 52 nanograms. These prostaglandins cause the smooth muscle of the uterus to contract, helping shed the lining. When production is unusually high, the contractions become more intense, which is why some people experience severe menstrual cramps. The drop in progesterone at the end of the cycle is the hormonal trigger that unleashes this surge.
Labor and Cervical Changes
Prostaglandins play a well-established role in labor, but the picture is more nuanced than previously thought. During infection-driven preterm labor, COX-2 ramps up dramatically in cervical tissue, and levels of multiple prostaglandins (E2, F2α, D2, and prostacyclin) rise significantly. This surge softens and dilates the cervix.
Normal term labor, however, tells a different story. Research in animal models has shown that cervical prostaglandin levels and the enzymes that produce them don’t necessarily increase during routine cervical ripening at term. This suggests that while prostaglandins are clearly involved in infection-related preterm birth, the cervix may ripen through other mechanisms during a healthy, full-term labor. Prostaglandins from other sources, like the uterus or fetal membranes, may still contribute, but local cervical production doesn’t appear to be the primary driver.
Stomach and Digestive Protection
Your stomach lining constantly produces prostaglandin E2 as a form of self-defense. This prostaglandin does three things simultaneously: it slows acid secretion, stimulates the production of protective mucus, and promotes bicarbonate release that neutralizes acid at the mucosal surface. COX-1 handles most of this baseline production.
Eating a meal normally boosts prostaglandin production in the stomach and duodenum, a process sometimes called adaptive cytoprotection. People with duodenal ulcers appear to have a defect in this post-meal prostaglandin surge, which may leave their mucosa more vulnerable to acid damage. This is also why NSAIDs that block COX-1 carry a risk of stomach ulcers. By shutting down the prostaglandin production that maintains the stomach’s protective barrier, these drugs leave the lining exposed to its own acid. Selective COX-2 inhibitors were developed specifically to reduce inflammation without disrupting this gastric defense system.
Kidney Blood Flow
The kidneys use prostaglandins as a safety valve. Under normal conditions, prostaglandin production in the kidneys is modest. But when blood pressure drops or cardiac output falls, the kidneys face a threat: vasoconstrictor signals from the nervous system and the renin-angiotensin system try to redirect blood away from the kidneys to preserve flow to the heart and brain.
Prostaglandins counteract this. When cardiac output drops, renal prostaglandin synthesis increases alongside renin secretion and sympathetic nerve activity. The prostaglandins dilate blood vessels within the kidney, keeping renal blood flow and filtration relatively stable despite the body-wide squeeze. This is why NSAIDs can be particularly dangerous for people with heart failure, dehydration, or kidney disease. Blocking prostaglandin production removes the kidney’s ability to protect its own blood supply when it’s under stress.
Blood Vessels and Clotting
The cells lining your blood vessels, called endothelial cells, release a prostaglandin called prostacyclin when stimulated by thrombin, the enzyme that drives blood clot formation. This creates a built-in feedback loop: when a vessel is injured and clotting begins, thrombin generated at the injury site triggers prostacyclin release from nearby healthy endothelial cells. Prostacyclin prevents platelets from clumping, effectively building a fence around the clot and keeping it from spreading beyond the injury.
Resting endothelial cells don’t produce detectable amounts of prostacyclin, and common platelet activators like ADP and epinephrine don’t trigger its release. The stimulus needs to come from something that signals active clotting or tissue disruption. This selective release mechanism ensures that prostacyclin shows up precisely when and where it’s needed to keep clot formation under control.
How NSAIDs Block the Process
Nonsteroidal anti-inflammatory drugs work by inhibiting the COX enzymes, cutting off prostaglandin production at its source. Traditional NSAIDs like ibuprofen and aspirin block both COX-1 and COX-2. This reduces pain and inflammation (by suppressing COX-2) but also disrupts the protective prostaglandins in the stomach and kidneys (by suppressing COX-1). Analysis of NSAID selectivity across human tissues confirms that gastrointestinal side effects correlate directly with how strongly a given drug inhibits COX-1.
COX-2 selective inhibitors were designed to target only the inflammation-related enzyme, sparing COX-1 and its protective functions. They do reduce stomach complications, though they come with their own cardiovascular trade-offs. The balance between these two enzyme targets remains central to how anti-inflammatory drugs are developed and prescribed.