Interleukin-1 family

Based on Wikipedia: Interleukin-1 family

In 1943, a scientist named Eli Menkin began injecting rabbits with proteins extracted from their own abdominal fluid. What he was really chasing was an answer to one of medicine's oldest questions: why do we get fevers?

The answer would take decades to fully unravel, but it led to the discovery of a family of molecules that sit at the very heart of how your body fights infection, heals wounds, and—when things go wrong—attacks itself.

These molecules are called interleukins, and the family we're exploring today, the Interleukin-1 family, might be thought of as your immune system's fire department. Except instead of putting out fires, they start them. Deliberately. Because sometimes, controlled burning is exactly what you need.

What Exactly Are Cytokines?

Before we dive deeper, let's establish what we're actually talking about. Cytokines are small proteins that cells release to communicate with each other. Think of them as text messages between cells—short, specific signals that trigger particular responses.

The word "interleukin" literally means "between white blood cells," which gives you a hint about their primary job. These are the molecules that coordinate immune responses, telling white blood cells where to go, what to do when they get there, and when to calm down.

The Interleukin-1 family contains eleven members, each with its own personality. Some are agitators, stirring up inflammation. Others are peacemakers, trying to calm things down. Understanding who does what is crucial to understanding how your body responds to everything from a paper cut to a viral infection.

The Discovery: Chasing Fever

The story of interleukin-1 begins with fever research. Between 1943 and 1948, Menkin and another scientist, Paul Beeson, were systematically investigating what makes body temperature rise during infection. They knew that certain proteins released by immune cells could trigger fever, but identifying exactly which proteins was like trying to find a specific grain of sand on a beach.

For decades, researchers in this field were essentially describing the same phenomenon using different names. Macrophages—large immune cells that engulf invaders—were releasing something powerful, and lymphocytes—smaller immune cells that coordinate responses—were releasing something too. The terminology was becoming chaotic.

In 1979, scientists agreed to impose some order. They coined the term "interleukin" specifically to streamline what had become a confusing mess of names for similar substances. Interleukin-1 would refer to the macrophage product. Interleukin-2 would refer to the lymphocyte product. Simple, elegant, and completely devoid of any actual knowledge about what these molecules looked like at the chemical level.

That changed in 1985. Using newly developed genetic techniques, researchers isolated the actual DNA sequences encoding interleukin-1 from a library of macrophage genes. To everyone's surprise, there wasn't one interleukin-1—there were two. They were related but distinct, like cousins rather than twins. These became known as interleukin-1 alpha and interleukin-1 beta, or IL-1α and IL-1β for short.

The Family Tree

Today we know the family has eleven members, and their relationships tell an evolutionary story written in DNA.

Nine of these family members cluster together on human chromosome two. When scientists examine this region, they can trace how it evolved: a single ancestral gene duplicating itself over and over, each copy gradually accumulating mutations until they became distinct genes with distinct functions. It's like watching a family spread across generations, each branch developing its own characteristics while retaining the family resemblance.

The original gene was probably something like modern IL-1β. From it arose IL-1α, three variants called IL-36α, IL-36β, and IL-36γ, an antagonist called IL-36 receptor antagonist, IL-37, IL-38, and IL-1 receptor antagonist. These are the true blood relatives.

Two other family members—IL-18 and IL-33—live on entirely different chromosomes. They've been adopted into the family based on structural similarities and functional overlap rather than genetic lineage. They fold into similar shapes and interact with related receptors, so scientists group them together even though they may have evolved independently.

How These Molecules Are Made

Here's where things get biochemically interesting. Almost every member of this family is synthesized as what scientists call a precursor protein—a longer, inactive version that must be cut down to size before it can do its job.

This is unusual. Most proteins that cells want to export follow a predictable path. They're manufactured in a compartment called the endoplasmic reticulum, packaged in another compartment called the Golgi apparatus, and shipped out through well-defined export channels. It's like a factory with loading docks and delivery trucks.

The interleukin-1 family doesn't work that way. These proteins lack the molecular shipping label—called a signal peptide—that would direct them through the normal export pathway. Instead, they're made in the cell's general interior and exported through mechanisms scientists still don't fully understand. They're called "leaderless secretory proteins," which is a technical way of saying "we know they get out, but we're not entirely sure how."

This matters because it means the cell has multiple control points. First, should we make the precursor at all? Second, should we cut it into its active form? Third, should we release it? Each decision can be regulated independently, giving the body exquisite control over inflammation.

The Two Stars: IL-1α and IL-1β

IL-1α and IL-1β are the most studied family members because they were discovered first and because their effects are so dramatic. Both trigger inflammation, but they do it in subtly different ways.

IL-1α is what scientists call a "dual-function cytokine." It works both inside and outside the cell. Inside, portions of the IL-1α molecule can enter the nucleus and directly influence which genes get turned on. Outside, it binds to receptors on other cells and triggers inflammation the conventional way. It's like having an employee who can both write company memos and make announcements over the loudspeaker.

IL-1α is constantly present in certain cell types—particularly cells that line surfaces like skin and the digestive tract. It sits there, pre-made and waiting. When these cells die from injury or stress, they release their IL-1α contents, essentially screaming "damage here!" to the immune system. In this role, IL-1α acts as what immunologists call a damage-associated molecular pattern, or DAMP—a signal that something has gone wrong even in the absence of infection.

IL-1β works differently. It's not sitting around waiting; it has to be manufactured on demand. When immune cells encounter danger signals—like bacterial components or cellular debris from dying neighbors—they activate genes that produce IL-1β precursor. But this precursor is inactive. It requires a second signal to become functional.

That second signal comes from a remarkable molecular machine called the inflammasome.

The Inflammasome: A Molecular Safety Switch

The inflammasome is one of the most elegant safety mechanisms in biology. It ensures that IL-1β isn't released accidentally, because inappropriate inflammation can be just as dangerous as infection.

Here's how it works. The inflammasome is a protein complex that assembles inside cells only when certain danger signals are detected. When it assembles, it activates an enzyme called caspase-1. Caspase-1 is a molecular scissors that cuts the IL-1β precursor at a specific location, releasing the active, mature form.

So producing active IL-1β requires two independent events: first, something must trigger production of the precursor; second, something must trigger inflammasome assembly. This two-key system prevents accidental activation. You need both keys to launch the missile.

IL-18, another family member, uses the same system. Its precursor also requires caspase-1 cleavage to become active. This shared mechanism suggests that evolution found a good solution and applied it to multiple molecules.

The Peacemaker: IL-1 Receptor Antagonist

If IL-1α and IL-1β are the gas pedal for inflammation, IL-1 receptor antagonist—IL-1Ra for short—is the brake.

IL-1Ra binds to the same receptor as IL-1α and IL-1β, but it doesn't activate it. It just sits there, blocking the binding site, preventing the pro-inflammatory signals from getting through. It's like a key that fits the lock but won't turn it—and while it's stuck in there, no other key can get in either.

This antagonist is produced by many of the same cells that produce IL-1: macrophages, monocytes, neutrophils, and various tissue cells. The balance between IL-1 and IL-1Ra determines how much inflammation actually occurs. Too much IL-1 relative to IL-1Ra, and inflammation rages out of control. Too much IL-1Ra, and the body can't mount an effective response to genuine threats.

Interestingly, IL-1Ra is the only family member that follows the normal protein export pathway. It has a proper signal sequence and gets secreted through the standard endoplasmic reticulum to Golgi route. Perhaps this is because the body needs to export large quantities rapidly to control inflammation, and the conventional export machinery can handle higher volumes.

The importance of IL-1Ra becomes devastatingly clear in children born with mutations that prevent its production. This condition, called DIRA (deficiency of IL-1 receptor antagonist), causes severe inflammation of the skin and bones starting in infancy. Without the brake, the inflammatory accelerator pushes the body toward self-destruction.

What Inflammation Actually Does

When IL-1α or IL-1β successfully binds its receptor and triggers signaling, what happens?

The immediate cellular response involves activating transcription factors—proteins that enter the nucleus and turn on specific genes. Key players include NF-κB (nuclear factor kappa-B), AP-1, and p38 MAPK. These transcription factors upregulate hundreds of genes involved in inflammation, immunity, and tissue remodeling.

At the tissue level, this translates to the classic signs of inflammation: redness, heat, swelling, and pain. IL-1 increases the expression of adhesion molecules on the cells lining blood vessels, making them sticky so that immune cells can grab on and squeeze through into the tissue. It dilates blood vessels, increasing blood flow to the area. It sensitizes pain receptors, creating hyperalgesia—increased sensitivity to pain that makes you protect the injured area.

At the whole-body level, IL-1 is one of the molecules responsible for fever. It acts on the hypothalamus, the brain region that controls body temperature, essentially turning up the thermostat. This is why IL-1 is classified as an endogenous pyrogen—a fever-causing substance produced by the body itself rather than by invading microbes.

Fever, despite being uncomfortable, is generally helpful. Many pathogens reproduce more slowly at elevated temperatures, and immune cells work more efficiently when it's warm. The fever response is a calculated trade-off: spend extra energy heating the body to gain an advantage against infection.

Beyond Immunity: Metabolism and Obesity

Here's where the story takes an unexpected turn. IL-1 isn't just about fighting infection. It also appears to regulate metabolism and body weight.

In 1999, researchers discovered that leptin—the hormone that signals fullness and helps regulate body weight—works partly through IL-1. When they blocked IL-1 signaling in the brain, leptin stopped working properly. Animals ate more and couldn't regulate their body temperature as effectively.

Even more striking, mice genetically engineered to lack the IL-1 receptor develop obesity as they age. Not from birth, but as they mature—what scientists call "mature-onset obesity." This pattern suggests that IL-1 signaling helps maintain normal weight throughout life, and without it, the body gradually loses its ability to regulate energy balance.

Similar mature-onset obesity occurs in mice lacking interleukin-6, another inflammatory cytokine. The pattern suggests that the immune system and metabolic system are deeply intertwined—that the molecules controlling inflammation also help control how the body handles food and energy.

This connection might explain why obesity itself is associated with chronic low-grade inflammation. The relationship appears to be bidirectional: inflammation affects metabolism, and metabolic dysfunction promotes inflammation, creating a feedback loop that can be difficult to break.

The Receptor System

Understanding how IL-1 signals requires understanding its receptor, which is surprisingly complicated.

The main receptor is called IL-1 receptor type 1, or IL-1R1. When IL-1α or IL-1β binds to this receptor, it recruits a second protein called IL-1 receptor accessory protein, or IL-1RAcP. This coreceptor is essential—without it, binding occurs but no signal gets transmitted.

Once the receptor complex assembles, the intracellular portions come together and recruit adaptor proteins. The key adaptor is called MyD88 (myeloid differentiation primary response gene 88), a name that reflects its discovery in cells differentiating into myeloid immune cells. MyD88 recruits enzymes called IRAKs (interleukin-1 receptor-activated kinases), which kick off a cascade of chemical modifications that eventually activate the transcription factors mentioned earlier.

This signaling pathway is ancient and highly conserved. Similar systems exist in fruit flies and other organisms that diverged from humans hundreds of millions of years ago. The pathway is so fundamental to immunity that it's been preserved almost unchanged across vast evolutionary distances.

The Extended Family

Beyond the stars of the show, the IL-1 family includes several other interesting members.

IL-18 was initially identified as a factor that induces interferon-gamma, a cytokine crucial for fighting viral infections and intracellular bacteria. It shares structural features with the IL-1 family and uses a similar receptor system, though with its own specific receptor chains. IL-18 works particularly well in combination with IL-12, another cytokine, to drive what immunologists call cellular immunity—the branch of the immune system that destroys infected cells rather than just neutralizing free-floating pathogens.

IL-33, like IL-1α, acts as both a cytokine and a nuclear transcription factor. Also like IL-1α, its precursor form can function as a damage signal when released from dying cells. IL-33 is particularly important in allergic responses and in defending against parasitic worms—a role that reflects a different evolutionary pressure than the bacterial-fighting origins of IL-1β.

The IL-36 subfamily—IL-36α, IL-36β, and IL-36γ—share a receptor system and are particularly important in skin immunity. Their antagonist, IL-36 receptor antagonist, keeps them in check. Mutations affecting this balance can cause severe skin diseases, highlighting the importance of the agonist-antagonist equilibrium.

IL-37 stands out as a suppressor rather than a promoter of inflammation. While most family members push toward more inflammation, IL-37 pushes back. Its existence underscores the principle that the immune system is built on checks and balances, not just accelerators.

Medical Applications

Understanding the IL-1 family has led directly to new treatments for inflammatory diseases.

The most prominent example is anakinra, a pharmaceutical version of IL-1 receptor antagonist. It's manufactured using recombinant DNA technology—essentially engineering bacteria to produce human IL-1Ra—and is used to treat rheumatoid arthritis and several other inflammatory conditions.

The logic is straightforward: if a disease is caused by too much IL-1 signaling, provide extra antagonist to restore balance. In rheumatoid arthritis, where IL-1 drives joint destruction, blocking IL-1 can slow disease progression and reduce pain.

Anakinra has also proven valuable in DIRA, the genetic deficiency of IL-1Ra. For children born without the ability to make their own IL-1Ra, injections of the pharmaceutical version can be lifesaving, controlling inflammation that would otherwise be relentless and destructive.

Research continues into other family members as potential drug targets. The IL-36 pathway, for instance, is being investigated for skin diseases like psoriasis. IL-18 is being studied in the context of inflammatory bowel disease. Each family member represents a potential intervention point for diseases where that particular signal is out of balance.

The Bigger Picture

The interleukin-1 family illustrates several fundamental principles about how the immune system works.

First, redundancy. Multiple family members can trigger inflammation, ensuring that no single failure point can disable the entire system. If IL-1β doesn't work, IL-1α might compensate. If both are blocked, IL-18 or IL-33 might pick up some of the slack. Evolution has built in backup systems.

Second, balance. For almost every pro-inflammatory signal, there's an anti-inflammatory counterweight. IL-1Ra opposes IL-1. IL-36Ra opposes the IL-36 cytokines. IL-37 opposes inflammation generally. The system isn't designed to be always-on or always-off—it's designed to find the right level of response for each situation.

Third, integration. The IL-1 family doesn't work in isolation. These cytokines interact with other cytokine families, with the complement system, with the coagulation system, with the nervous system, with metabolic regulation. Inflammation is a whole-body phenomenon, and the molecules that control it are networked into virtually every physiological process.

Fourth, evolutionary conservation. The core mechanisms—the receptor systems, the signaling pathways, the inflammasome—are ancient. They existed before mammals, before vertebrates, probably before the split between animals and other complex life forms. We're using molecular machinery that has been refined over hundreds of millions of years.

Understanding this family of molecules matters not just for treating disease but for appreciating the remarkable sophistication of our immune systems. These eleven proteins, each precisely regulated, each with its own role, together orchestrate responses that protect us from infection while limiting the damage that overzealous immunity can cause.

The next time you run a fever, remember: you're experiencing interleukin-1 in action, doing exactly what it evolved to do. It's uncomfortable, yes. But it's also your body deploying one of its oldest and most refined defense mechanisms—one that scientists are still working to fully understand, eight decades after those first rabbit experiments began to reveal its secrets.