IL-1, short for interleukin-1, is a protein your immune system produces to trigger inflammation and coordinate the body’s defense against infection and injury. It is one of the most powerful inflammatory signals in the human body, responsible for familiar experiences like fever, swelling, and pain during illness. When IL-1 works correctly, it helps you fight off threats. When it’s overactive, it drives a wide range of inflammatory diseases.
The Two Main Forms of IL-1
IL-1 comes in two primary forms: IL-1 alpha and IL-1 beta. Both bind to the same receptor on cells and produce similar inflammatory effects, but they originate and behave differently.
IL-1 alpha is present inside many cell types and often gets released when cells are damaged or dying. Think of it as an alarm signal: when tissue is injured, the contents of dying cells spill out, and IL-1 alpha alerts the immune system that something is wrong. It doesn’t require much processing to become active, and its release is controlled by calcium-dependent enzymes called calpains.
IL-1 beta, by contrast, is produced mainly by immune cells like macrophages and monocytes. It starts as an inactive precursor and must be cut into its active form by a molecular machine called the inflammasome. Despite surface similarities, research in the Journal of Biological Chemistry has confirmed that the two forms use distinct secretory pathways to exit the cell. IL-1 beta relies on a pore-forming protein called gasdermin D to pass through the cell membrane, while IL-1 alpha does not.
How IL-1 Beta Gets Activated
The activation of IL-1 beta is a tightly controlled, two-step process. First, an immune cell detects a threat (a bacterial component, a viral signal, or tissue damage) and begins producing the inactive precursor, pro-IL-1 beta. This precursor sits inside the cell, doing nothing on its own.
The second step requires a danger signal that assembles the NLRP3 inflammasome, a protein complex made up of three key components: the sensor protein NLRP3, an enzyme called caspase-1, and an adaptor molecule called ASC. Once assembled, caspase-1 cuts pro-IL-1 beta into its mature, active form, which then exits the cell and begins driving inflammation in surrounding tissue. This two-step requirement acts as a safety mechanism, ensuring IL-1 beta is only released when the body faces a genuine threat.
How IL-1 Causes Fever
IL-1 beta is one of the body’s primary fever-inducing molecules. When released into the bloodstream during an infection, it travels to the brain and binds to receptors on the cells lining blood vessels in the hypothalamus, the brain’s thermostat. This binding triggers those cells to produce prostaglandin E2, the final chemical messenger that actually raises your body temperature.
Prostaglandin E2 works by silencing neurons in the hypothalamus that normally keep your temperature in check. These neurons continuously send inhibitory signals to heat-generating circuits deeper in the brainstem. When prostaglandin E2 binds to its receptor (EP3) on these neurons, it shuts them down, essentially releasing the brakes on heat production. Your body then ramps up thermogenesis through shivering, blood vessel constriction, and metabolic changes. This is why you feel cold and shivery at the start of a fever: your body is actively generating heat to reach a new, higher set point.
The Body’s Built-In Off Switch
Because IL-1 is so potent, the body produces its own counterbalance: IL-1 receptor antagonist, or IL-1Ra. This protein belongs to the same family as IL-1 and binds to the same receptor on cells, but it triggers no response. It simply blocks the receptor, preventing IL-1 from docking and sending its inflammatory signal. IL-1Ra acts as a natural anti-inflammatory brake, and animal studies using antibodies that neutralize it have shown it plays a critical role in preventing runaway inflammation in conditions like arthritis and colitis.
Some people are born without functional IL-1Ra, a rare genetic condition called DIRA (Deficiency of IL-1 Receptor Antagonist). Without this brake, IL-1 signaling runs unchecked from birth, causing severe skin pustules, bone inflammation, and organ enlargement.
Diseases Driven by IL-1
When IL-1 production or signaling goes wrong, the consequences range from periodic fevers to chronic joint destruction. A number of rare genetic diseases are caused by mutations that directly increase IL-1 activity. Three of the most studied, collectively called cryopyrin-associated periodic syndromes (CAPS), all stem from mutations in the NLRP3 gene that make the inflammasome overactive:
- Familial cold autoinflammatory syndrome (FCAS): cold-triggered hives, chills, joint pain, and fever
- Muckle-Wells syndrome: hearing loss, rash, joint pain, and recurrent fevers
- NOMID: the most severe form, involving chronic brain inflammation, vision and hearing loss, and joint damage from infancy
Familial Mediterranean fever, caused by mutations in a different gene (MEFV), produces intense chest and abdominal pain from inflammation of the membranes lining internal organs, along with recurring fevers. Other IL-1-driven conditions include TRAPS (prolonged fevers with painful, spreading rashes and eye inflammation) and Majeed syndrome (bone inflammation with anemia).
IL-1 also plays a central role in more common conditions. Gout, which affects millions of people, is fundamentally an IL-1-driven disease. When uric acid crystals deposit in a joint, they activate the NLRP3 inflammasome, triggering massive IL-1 beta release and the sudden, excruciating inflammation of a gout flare.
IL-1 and Heart Disease
One of the most significant discoveries about IL-1 in recent years came from a landmark trial called CANTOS, published in the New England Journal of Medicine. Researchers gave over 10,000 people who had already suffered a heart attack an antibody that specifically blocks IL-1 beta, without lowering cholesterol at all. Those receiving the treatment had a 15% lower rate of major cardiovascular events (heart attack, stroke, or cardiovascular death) compared to placebo. This was the first large-scale proof that targeting inflammation directly, independent of cholesterol, could reduce heart disease risk.
Medications That Block IL-1
The understanding of IL-1’s role in disease has led to targeted therapies. The most established is anakinra, a lab-made version of the body’s own IL-1Ra. It works the same way natural IL-1Ra does: binding the receptor and blocking IL-1 from activating it. Anakinra is FDA-approved for moderately to severely active rheumatoid arthritis in adults who haven’t responded to other treatments, for NOMID, and for DIRA.
Canakinumab takes a different approach. Rather than blocking the receptor, it’s an antibody that binds directly to IL-1 beta and neutralizes it before it can reach any cell. This is the drug used in the CANTOS cardiovascular trial and is approved for several autoinflammatory conditions.
Normal IL-1 Levels
IL-1 beta can be measured in blood, though it’s not a routine test. In healthy individuals, serum IL-1 beta levels are typically 6.7 picograms per milliliter or less, according to ARUP Laboratories reference ranges. Elevated levels suggest active inflammation but aren’t specific to any single condition. Clinicians typically use IL-1 levels alongside other inflammatory markers and clinical symptoms to build a complete picture rather than relying on them as a standalone diagnostic tool.