Interleukins are a large family of signaling proteins that immune cells use to communicate with each other and coordinate the body’s defense against infection, injury, and disease. As of the most recent count, at least 33 distinct proteins carry the interleukin label, though many belong to subfamilies of related molecules with overlapping but distinct jobs.1Europe PMC. Historical insights into cytokines Some interleukins ramp up inflammation to fight off invaders; others dial it back to prevent the immune system from damaging healthy tissue. Their reach extends well beyond infection, influencing everything from allergies and autoimmune disease to how you feel when you exercise and why illness makes you want to sleep.
How Interleukins Deliver Their Messages
An interleukin works by attaching to a specific receptor on the surface of a target cell, much like a key fitting a lock. That binding event sets off a chain of signals inside the cell that ultimately changes which genes get switched on or off. One well-studied example is the pathway triggered by IL-10, where the interleukin docks with its receptor and activates enzymes called Jak1 and Tyk2, which in turn activate a transcription factor called STAT3. STAT3 then moves into the cell’s nucleus and turns on genes that suppress inflammation.2Journal of Biological Chemistry. Interleukin-10 Receptor Signaling through the JAK-STAT Pathway Different interleukins use variations on the same basic machinery, but the downstream effects differ dramatically depending on which receptor is involved and which cell type is receiving the signal.
The Inflammation Starters
When the body detects a pathogen or tissue damage, certain interleukins act as the first alarm bells. IL-1β is one of the most potent. Once released, it triggers a cascade that activates genes involved in inflammation, recruits immune cells to the site of infection, and helps bridge the gap between the fast-acting innate immune system and the slower, more targeted adaptive immune system.3PubMed. Interleukin-1beta (IL-1beta) processing pathway IL-1β is also activated by non-microbial danger signals, which is why you get inflammation after a sprained ankle even though no bacteria are involved.
IL-6 is another major pro-inflammatory player, but with a wider job description. In the liver, it is the key driver of the acute phase response, the body’s system-wide alarm that produces proteins like C-reactive protein (CRP) and serum amyloid A. These acute phase proteins help contain infection and flag damaged tissue for cleanup.4PubMed. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes Doctors measure CRP in blood tests as a general marker of inflammation, and that measurement is essentially a downstream readout of IL-6 activity.
The Inflammation Brakes
An immune system that only knows how to accelerate would destroy the body it is trying to protect. IL-10 is one of the most important braking signals. It works by activating STAT3, which in turn switches on genes that suppress inflammation. One of those genes blocks the activity of NF-κB, a master switch for pro-inflammatory gene expression.5Frontiers in Immunology. The multifaceted nature of IL-10: regulation, role in immunological homeostasis and its relevance to cancer, COVID-19 and post-COVID conditions In practical terms, IL-10 tells activated immune cells to stand down once the threat is under control. When IL-10 signaling is defective, chronic inflammatory conditions can develop because the immune response never fully resolves.
Directing the Adaptive Immune Response
Your adaptive immune system, the branch that learns to recognize specific pathogens and remember them for future encounters, relies heavily on interleukins for its development and coordination. IL-2 is central to this process. It supports the growth and survival of regulatory T cells (which prevent autoimmune attacks) and also drives the differentiation of helper T cells, cytotoxic “killer” T cells, and memory T cells that provide lasting immunity after an infection or vaccination.6Immunity. Interleukin-2 signaling in the regulation of T cell biology in autoimmunity and cancer
IL-4 and IL-13 steer the immune response in a different direction entirely. These two related interleukins push naïve helper T cells toward what immunologists call a Th2 response, which is specialized for fighting parasites and, less helpfully, for driving allergic reactions. IL-4 also instructs B cells to switch their antibody production to IgE, the antibody class responsible for allergic symptoms like hives, sneezing, and anaphylaxis.7Frontiers in Immunology. Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes In people with allergies to house dust mites, for example, IL-4 and IL-13 play a central role in sustaining the overproduction of IgE and the airway inflammation that follows.8PubMed Central. Dendritic cell-CD4+ T cell interaction: The differential role of IL-4/IL-13 in serum IgE levels in house dust mite allergic patients
The IL-23 and IL-17 Axis in Autoimmune Disease
Not every interleukin pathway defends against external threats. The IL-23/IL-17 axis is a powerful example of an immune circuit that, when misdirected, drives autoimmune disease. IL-23 promotes the development of a subset of helper T cells called Th17 cells, which produce IL-17 and other inflammatory molecules. Under normal circumstances, this pathway helps protect against fungal infections by recruiting neutrophils and macrophages to infection sites.9Frontiers in Cellular and Infection Microbiology. The Role of the Interleukin-17 Axis and Neutrophils in the Pathogenesis of Endemic and Systemic Mycoses
The trouble arises when this axis fires without an actual fungal or bacterial target. In animal models of inflammatory bowel disease and multiple sclerosis, blocking IL-23 or its downstream signals IL-17 and IL-6 significantly suppressed disease development.10PubMed Central. The IL-23/IL-17 axis in inflammation The same axis has been implicated in systemic lupus erythematosus, where IL-23-driven Th17 activity contributes to the tissue damage characteristic of the disease.11PubMed Central. IL-12 and IL-23/Th17 axis in systemic lupus erythematosus
Cytokine Storms and Runaway Inflammation
The phrase “cytokine storm” entered public awareness during the COVID-19 pandemic, but the phenomenon has been recognized in sepsis, certain cancers, and reactions to some therapies for decades. It refers to a situation where the immune system’s inflammatory signals spiral out of control, damaging the body’s own tissues faster than any pathogen could. IL-6 is a central culprit. It directly affects the cells lining blood vessels, triggering them to release additional inflammatory signals and activate the blood clotting cascade. The result can be widespread vascular leakage and abnormal clotting.12PubMed Central. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms
In sepsis, the massive release of cytokines including IL-6 can cause blood pressure to collapse, leading to organ failure and, in severe cases, death.13PubMed. Interleukin-6 in sepsis and capillary leakage syndrome This is why drugs that block IL-6 signaling, like tocilizumab, became part of the treatment toolkit for severe COVID-19 and remain used in other conditions where excessive inflammation threatens life.
Why Being Sick Makes You Feel Terrible
The fatigue, loss of appetite, social withdrawal, and general misery you feel during an infection are not just side effects of the pathogen itself. They are an organized behavioral strategy orchestrated by pro-inflammatory interleukins acting on the brain. IL-1β and IL-6 reach the brain through two routes: via nerves that detect inflammation at the infection site, and through the bloodstream.14PubMed Central. Cytokine, sickness behavior, and depression Once in the brain, these cytokines trigger fever, suppress appetite, and reduce the desire to move around.
Animal studies have shown that IL-1β and IL-6 injected directly into the brain produce dose-dependent increases in body temperature and decreases in voluntary activity. At doses that individually have little effect, the two interleukins act together to induce fever and loss of appetite, demonstrating that they work synergistically.15Brain, Behavior, and Immunity. Interleukin (IL)-6 and IL-1β act synergistically within the brain to induce sickness behavior and fever in rats Blocking IL-6 signaling specifically in the brain speeds recovery from this sickness behavior, suggesting that this interleukin is not just a marker of illness but an active driver of how bad you feel.16PubMed Central. Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior This research has implications for understanding chronic fatigue and depression-like symptoms in people with persistent inflammatory conditions.
Exercise and the Surprising Role of IL-6 as a Myokine
IL-6 has a reputation as an inflammatory troublemaker, but during physical exercise it plays a strikingly different role. Working skeletal muscles produce and release large amounts of IL-6 into the bloodstream, with levels rising up to 100-fold during prolonged or intense exercise.17PubMed. Muscle as an endocrine organ: focus on muscle-derived interleukin-6 In this context, IL-6 functions more like a hormone than a distress signal. It acts on the liver and fat tissue to help maintain blood sugar levels and promote fat breakdown during prolonged activity.18PubMed Central. Muscle-derived interleukin-6: possible biological effects Muscle-derived IL-6 may even counteract the effects of other pro-inflammatory cytokines, which is one reason regular exercise is associated with reduced chronic inflammation despite the fact that each workout temporarily raises IL-6.
Research has shown through genetic experiments that the majority of circulating IL-6 detectable during exercise originates from muscle, and that its capacity to increase exercise endurance depends on signaling through bone cells. Muscle-derived IL-6 signals to osteoblasts, which in turn release a hormone called osteocalcin that feeds back to muscle fibers and promotes their uptake of nutrients during exertion.19JCI Insight. Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts This muscle-to-bone-to-muscle loop was a genuine surprise when it was discovered and is a vivid illustration of how the same interleukin can have completely different effects depending on the context.
Interleukins as Diagnostic Markers
Because interleukin levels rise and fall in predictable patterns during illness, they have become useful diagnostic tools. IL-6 measurement in particular has proven valuable for identifying sepsis, a condition where rapid diagnosis can be life-saving. A systematic review and meta-analysis found that serum IL-6 had a pooled sensitivity of about 80% and specificity of about 85% for diagnosing sepsis overall. In newborns, specificity was especially high at around 91%.20PubMed Central. Accuracy of serum interleukin (IL)-6 in sepsis diagnosis: a systematic review and meta-analysis
IL-6 levels also track with disease severity. In one study, serum IL-6 was significantly higher in patients with septic shock compared to those with milder forms of sepsis, and the levels correlated with clinical severity scores and heart rate.21PubMed Central. Detection of Serum Interleukin-6/10/18 Levels in Sepsis and Its Clinical Significance Emergency departments increasingly use IL-6 alongside traditional markers to make faster decisions about treatment, especially when combined with other clinical measurements like blood pressure and kidney function tests.22PubMed Central. Diagnostic and Prognostic Value of Interleukin-6 in Emergency Department Sepsis Patients
Drugs That Target Interleukins
The discovery that specific interleukins drive specific diseases has led to a growing class of drugs designed to block or mimic them. Some of the most successful target the IL-23/IL-17 axis in psoriasis and psoriatic arthritis. IL-23 inhibitors such as guselkumab, tildrakizumab, and risankizumab have emerged as safe and effective treatments for moderate-to-severe plaque psoriasis, requiring less frequent dosing than IL-17 inhibitors and carrying a lower risk of yeast infections or inflammatory bowel disease flares.23PubMed Central. Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review
IL-17A inhibitors have shown rapid results in psoriasis, quickly suppressing the disease’s characteristic gene activity and producing high clinical response rates. Their effectiveness in joint disease, however, has been more modest, suggesting IL-17A plays a bigger role in skin inflammation than in joint inflammation for most patients.24PubMed Central. Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis A meta-analysis of eight trials covering over 2,700 patients found that various interleukin inhibitors significantly outperformed placebo for psoriatic arthritis across multiple measures of clinical improvement.25Journal of Clinical Rheumatology. A Systematic Review and Meta-analysis of Efficacy and Safety of Novel Interleukin Inhibitors in the Management of Psoriatic Arthritis
Interleukins in Cancer Treatment
IL-2 was one of the first interleukins used as a cancer therapy. It has been approved for metastatic kidney cancer and metastatic melanoma, where it can induce complete and lasting tumor regression in some patients.26PubMed Central. Role of IL-2 in cancer immunotherapy The logic is straightforward: IL-2 stimulates the killer T cells and natural killer cells that can recognize and destroy cancer cells. In practice, however, the drug’s broader use has been held back by severe toxicity, because IL-2 receptors exist on many cell types and flooding the body with the protein causes widespread immune activation.27Molecular Cancer Therapeutics. Abstract IA012: REGN10597: A PD-1-targeted, receptor-masked wild type IL-2 with improved therapeutic window for cancer immunotherapy
IL-6 presents a more complicated picture in oncology. It can both promote and inhibit cancer immunotherapy depending on the context, making it a double-edged sword for researchers trying to target it.28Cytokine & Growth Factor Reviews. Interleukin-6 (IL-6)-associated tumor microenvironment remodelling and cancer immunotherapy Similarly, IL-33 behaves differently depending on where it is found: when expressed inside tumor cells, it seems to boost the immune response against the cancer through killer T cells and natural killer cells, but when present in the tissue surrounding the tumor and in blood, it tends to suppress immunity by supporting regulatory T cells that dampen anti-tumor activity.29PubMed. Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy These location-dependent effects are a recurring theme in interleukin biology and one reason cancer immunotherapy remains so challenging to get right.
Aging and Low-Grade Chronic Inflammation
As people age, the body tends to develop a state of chronic, low-level inflammation sometimes called “inflammaging.” This slow burn is driven in part by senescent cells, which are old, damaged cells that stop dividing but refuse to die. Instead, they release a cocktail of inflammatory signals known as the senescence-associated secretory phenotype, which includes several interleukins.30PubMed Central. Cellular Senescence, Inflammaging and Cardiovascular Disease Over years, this steady drip of pro-inflammatory interleukins contributes to tissue remodeling and is linked to cardiovascular disease, metabolic dysfunction, and other age-related conditions. It is a fundamentally different problem from the acute, purposeful inflammation that resolves after an infection, and it represents one of the frontiers of aging research.
Interleukins at the Gut Barrier
The intestine is the body’s largest interface with the outside world, and interleukins are critical to keeping that barrier intact. IL-22, a member of the IL-10 family, plays a particularly important role in intestinal health. It strengthens the gut’s physical barrier, helps defend against bacterial and fungal pathogens that enter the digestive tract, and modulates inflammation in the intestinal lining.31PubMed Central. Interleukin-22 Signaling in the Regulation of Intestinal Health and Disease Dysregulation of IL-22 signaling has been implicated in several gastrointestinal diseases, making it a target of ongoing therapeutic interest.
Engineered Interleukins and the Future of Therapy
The toxicity problems that have plagued natural interleukin therapies, especially IL-2 in cancer treatment, have spurred a wave of protein engineering aimed at creating smarter versions of these molecules. One approach involves “shielded” cytokines that remain inactive in general circulation but become activated specifically within the tumor microenvironment, reducing the collateral damage to healthy tissue.32PubMed Central. Protein engineering to overcome limitations of key cytokines in cancer immunotherapy: current approaches and future perspectives Other strategies include extending the protein’s lifespan in the blood so lower doses can be used, or engineering the molecule to preferentially activate killer immune cells rather than regulatory cells that could suppress anti-tumor immunity.
One promising design fuses IL-2 with an antibody fragment that biases the protein’s activity toward immune effector cells rather than the regulatory T cells that tend to protect tumors. In preclinical testing, this fusion protein expanded the desired killer cell populations and produced superior anti-tumor activity compared to unmodified IL-2, without the severe toxicities that limit the natural version.33PubMed Central. Engineered cytokine/antibody fusion proteins improve delivery of IL-2 to pro-inflammatory cells and promote antitumor activity This kind of precision engineering reflects a broader shift in immunotherapy: rather than flooding the immune system with a blunt signal and hoping for the best, the goal is to deliver the right message to the right cells in the right place. Given the complexity interleukins display across different tissues and disease states, that precision cannot come soon enough.