Cytokines are tiny proteins that cells release to send messages to other cells, and nearly every step of an immune response runs on them. The redness and swelling around a cut, a fever, and the urge to stay in bed during the flu are all cytokine messages at work.1IntechOpen. Perspective Chapter: Cytokine-mediated Acute Phase Response and Protein Synthesis2PubMed Central. Cytokine, Sickness Behavior, and Depression The same signals that protect you can cause harm when too many are released or they are not switched off, which is why some of today’s arthritis and COVID-era treatments work by blocking them.
The Main Cytokine Messengers and How Cells Read Them
Many cytokines are called interleukins, shortened to IL plus a number, such as IL-1 or IL-6. Three of them lead the way in inflammation: IL-1, IL-6 and TNF-alpha, often written just TNF.3IntechOpen. Perspective Chapter: Cytokine-mediated Acute Phase Response and Protein Synthesis Interferons are another group. Interferon-gamma in particular switches on immune cells that destroy germs hiding inside cells.4PubMed Central. IFN-γ-Driven macrophage responses in the immunity to Mycobacterium tuberculosis and Mycobacterium leprae
Cytokines act by binding to specific receptors on the surface of a target cell, like a key fitting a lock.5PubMed Central. The molecular details of cytokine signaling via the JAK/STAT pathway A cell only responds if it carries the matching receptor, so the same cytokine can affect some tissues and ignore others.
Binding sets off a relay of chemical switches inside the cell that tells it to grow, change, or die.6PubMed Central. The molecular details of cytokine signaling via the JAK/STAT pathway For many cytokines this relay, called the JAK-STAT pathway, ends with signals reaching the cell’s genes.7PubMed Central. The JAK/STAT signaling pathway: from bench to clinic IL-1 and TNF use a different relay that switches on a master inflammation control inside the cell.8PubMed Central. TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme
Cytokines also differ from hormones. Hormones usually travel far through the blood from one gland. Most cytokines act locally, on neighbouring cells, over short times. In severe illness, though, cytokines spill into the blood and act body-wide, and that spillover is what links a local infection to whole-body symptoms.
One cytokine can trigger many different effects, and several different cytokines can trigger the same effect.9PubMed Central. Multifarious Determinants of Cytokine Receptor Signaling Specificity That happens because receptors share parts, and the cell has only four JAK and seven STAT switches to pass messages on.10PubMed Central. Multifarious Determinants of Cytokine Receptor Signaling Specificity So blocking a single cytokine rarely shuts down a whole response, while blocking a shared switch affects many at once.
How Cytokines Start Inflammation at an Injury or Infection
When immune cells recognise signs of germs or damaged tissue, they release cytokines.11IntechOpen. Perspective Chapter: Cytokine-mediated Acute Phase Response and Protein Synthesis IL-6 is made not only by immune cells but also by blood vessel lining cells and connective tissue cells, so many kinds of cells join in.12PubMed Central. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms IL-1 and TNF prompt yet more IL-6 release, so the alarm amplifies itself.13PubMed Central. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms
IL-1 and TNF activate the cells lining blood vessels.14IntechOpen. Perspective Chapter: Cytokine-mediated Acute Phase Response and Protein Synthesis The vessels become leakier, letting fluid into the tissue, which you see as swelling. Increased blood flow brings the redness and warmth around the area.
White blood cells cannot simply leave the bloodstream anywhere. They exit only where the vessel lining has been activated, which is why the fight stays concentrated at the injury and not spread across the body. Activated lining cells put sticky molecules on their inner face, so passing white cells first slow down and roll along the wall before gripping it.
Chemokines are cytokines that act as homing signals, directing white blood cells out of blood vessels to where they are needed.15PubMed. Leukocyte extravasation: chemokine transport and presentation by the endothelium Neutrophils grip the vessel wall and crawl, even against the blood flow, toward the chemokine trail.16PubMed Central. Crossing the Vascular Wall: Common and Unique Mechanisms Exploited by Different Leukocyte Subsets during Extravasation Some T cells pick up chemokines stored inside vessel lining cells at the point of contact to squeeze through.17PubMed. Transendothelial migration of lymphocytes mediated by intraendothelial vesicle stores rather than by extracellular chemokine depots Neutrophils, a type of white blood cell, arrive at an infected wound within hours, and pus is largely dead neutrophils.
IL-6 also sends a signal to the liver, telling it to make a set of emergency proteins, including C-reactive protein (CRP) and fibrinogen, a clotting protein.18PubMed Central. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms That makes a CRP blood test an indirect readout of how much inflammation IL-6 is driving. CRP rises with infection, injury, surgery and chronic inflammatory diseases. It shows that inflammation is present but not what caused it, so doctors track it over time to see whether inflammation is falling.
Why Cytokines Make You Feel Sick
IL-1 contributes to fever during infection.19IntechOpen. Perspective Chapter: Cytokine-mediated Acute Phase Response and Protein Synthesis IL-1 and IL-6 act on temperature-sensing nerve cells in the brain to raise the body’s set point.20PubMed Central. Cytokine, Sickness Behavior, and Depression That is why you shiver and feel cold while your temperature climbs to the new setting.
Giving people or animals IL-1 or TNF reproduces all the general symptoms of illness: fever, eating less, less activity, and withdrawing from others.21PubMed Central. Cytokine, Sickness Behavior, and Depression So much of how bad you feel with flu comes from your own cytokines, not directly from the virus.22PubMed Central. Cytokine, Sickness Behavior, and Depression This state is thought to be a built-in drive that promotes recovery.23PubMed. Cytokine-induced sickness behavior IL-1 also triggers the brain’s stress chain that raises cortisol from the adrenal glands.24PubMed Central. Cytokine, Sickness Behavior, and Depression Feeling sick and withdrawn this way saves energy for the immune response.
Common fever medicines work by lowering the brain’s raised set point. They ease discomfort without stopping the immune response itself. A mild fever is often a normal sign of cytokines at work, though a high or persistent fever still needs medical attention.
How Cytokines Steer the Targeted Immune Response
When helper T cells are first activated, they mature into different types that each release their own set of cytokines.25PubMed Central. T Helper Cell Differentiation, Heterogeneity, and Plasticity The cytokines in their surroundings help push them toward one type or another, such as Th1, Th2 or Th17.26PubMed. An insight into molecular mechanisms of human T helper cell differentiation IL-12 from immune cells favours the Th1 type that fights germs inside cells.27PubMed Central. Anti- and Pro-inflammatory Roles of TGF-β, IL-10, and IL-22 In Immunity and Autoimmunity
The types suit different threats. Th1 responses suit viruses and germs living inside cells. Th2 responses suit parasites and are involved in allergies. Th17 responses suit some bacteria and fungi and feature in some autoimmune diseases. A mismatched or misdirected response can cause disease.
Interferon-gamma switches on macrophages, the immune system’s large germ-eating cells, so they can kill bacteria such as those causing tuberculosis.28PubMed Central. IFN-γ-Driven macrophage responses in the immunity to Mycobacterium tuberculosis and Mycobacterium leprae It also helps macrophages break down swallowed germs and show pieces of them to T cells.29PubMed Central. IFN-γ-Driven macrophage responses in the immunity to Mycobacterium tuberculosis and Mycobacterium leprae
Timing matters too. The first time a helper T cell meets a germ, the choice of type is still being made, so building a suitable response takes days. Memory T cells left after vaccination release interferon-gamma quickly on re-exposure, rapidly activating other defenders.30PubMed Central. Memory T Cell-Derived interferon-γ Instructs Potent Innate Cell Activation For Protective Immunity Because these cells have already been shaped, that speed difference is much of why a repeat exposure often passes with mild symptoms or none.
How Cytokines Switch Inflammation Off
The body actively sends stop signals and cleanup orders. IL-10 and TGF-beta stop macrophages producing TNF and IL-1.31PubMed. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10 They work differently: IL-10 destroys the cell’s instructions for making those cytokines, while TGF-beta mainly blocks their assembly.32PubMed. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10 IL-10 also lowers IL-12, damping the Th1 response.33PubMed Central. Anti- and Pro-inflammatory Roles of TGF-β, IL-10, and IL-22 In Immunity and Autoimmunity
TGF-beta stops immune cells that react to your own tissues from multiplying.34PubMed Central. Anti- and Pro-inflammatory Roles of TGF-β, IL-10, and IL-22 In Immunity and Autoimmunity Regulatory T cells use IL-10 and TGF-beta to suppress other T cells, and allergy shots can create them.35PubMed Central. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells
The body also makes fat-derived molecules called resolvins and related mediators that reduce neutrophil influx and lower inflammatory cytokines.36PubMed Central. Resolvins, Specialized Pro-Resolving Lipid Mediators and their Potential Roles in Metabolic Diseases They also help macrophages clear dead neutrophils and bacteria.37PubMed Central. Resolvins, Specialized Pro-Resolving Lipid Mediators and their Potential Roles in Metabolic Diseases Ending inflammation is an active process, and when the stop signals fail, inflammation can linger and turn chronic.
Calming cytokines are not simply good. Too much suppression too early can leave an infection unfinished, because the inflammatory response is also what clears germs. Too little leaves tissue exposed to ongoing damage from the body’s own weapons.
What a Cytokine Storm Is and Why It Is Dangerous
A cytokine storm is a body-wide surge of inflammatory cytokines in the blood, typically IL-1, IL-6, IL-18, interferon-gamma and TNF.38PubMed Central. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms A high IL-6 level is its hallmark.39PubMed Central. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms It has been seen in severe COVID-19, after CAR-T cancer therapy, and in an immune disorder called HLH.40PubMed Central. Deep insight into cytokine storm: from pathogenesis to treatment
Normal inflammation is local and self-limiting. A storm is body-wide and self-amplifying. Symptoms include high fever, low blood pressure and trouble breathing, and it is a medical emergency treated in hospital.
The causes differ. In severe COVID-19 the trigger is a virus the immune system struggles to control, so the alarm keeps being renewed. After CAR-T therapy the trigger is the treatment itself: engineered immune cells that attack cancer release large amounts of cytokines as they multiply. In HLH, the immune system’s own braking mechanisms are faulty, so activation keeps going once started, often after an infection sets it off.
The loop is literal. Cytokines can cause inflammatory cell death, and dying cells release more cytokines.41PubMed Central. The ‘Cytokine Storm’: molecular mechanisms and therapeutic prospects That can drive life-threatening damage to tissues and organs.42PubMed Central. The ‘Cytokine Storm’: molecular mechanisms and therapeutic prospects
IL-6 loosens the joints between vessel lining cells, causing blood vessels to leak.43PubMed Central. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms In lab tests on human lung vessel cells, IL-6 working with its partner receptor and IL-1 completely broke down the vessel barrier.44PubMed. Simultaneous Targeting of IL-1-Signaling and IL-6-Trans-Signaling Preserves Human Pulmonary Endothelial Barrier Function During a Cytokine Storm-Brief Report In the body, that means fluid can flood the lungs. IL-6 also switches on blood clotting, speeding the formation of clots.45PubMed Central. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms
Chronic inflammation is the slow version. Low-level cytokine signals can persist for years, and IL-6 is linked to autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease.46PubMed. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer
Medicines That Block Cytokines
Antibody drugs that block IL-6 or its receptor work in rheumatoid arthritis.47PubMed. Underpinning IL-6 biology and emphasizing selective JAK blockade as the potential alternate therapeutic intervention for rheumatoid arthritis They can lower white blood cell and platelet counts and raise liver enzyme levels.48PubMed. Underpinning IL-6 biology and emphasizing selective JAK blockade as the potential alternate therapeutic intervention for rheumatoid arthritis Blocking IL-6 also helped in lab models of several autoimmune diseases and inflammation-linked cancer.49PubMed. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer
JAK inhibitors are pills, such as tofacitinib and baricitinib, that block the JAK relay that many cytokines share.50PubMed. Underpinning IL-6 biology and emphasizing selective JAK blockade as the potential alternate therapeutic intervention for rheumatoid arthritis In rheumatoid arthritis trials, tofacitinib reduced disease activity, improved daily function and slowed joint damage.51PubMed Central. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases It also worked in people whose earlier injected antibody drugs had failed.52PubMed Central. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases
Antibody drugs are proteins, so they are given by injection or infusion instead of as pills, because digestion would break them down. JAK inhibitors are small molecules taken as pills, which some patients find easier. Benefit usually builds over weeks, not days, so a patient and doctor judge the drug after a trial period. Doctors monitor blood counts and liver tests during treatment because of the side effects above.
Blocking cytokines also blunts normal germ defenses. Doctors usually screen for tuberculosis and hepatitis before starting, and because fever may be muted, it is worth reporting feeling unwell early.
Another approach tunes a cytokine instead of blocking it. Scientists are engineering IL-2 variants that act on calming regulatory T cells to treat autoimmunity, or on killer cells to fight cancer.53PubMed. Engineering IL-2 for immunotherapy of autoimmunity and cancer Some changed versions avoid boosting regulatory T cells so they work better against tumours.54PubMed. Site-specific pegylated IL2 mutein with biased IL2 receptor binding for cancer immunotherapy
How Viruses and Tumours Hijack Cytokines
Large DNA viruses such as herpesviruses and poxviruses carry their own versions of cytokines and receptors.55PubMed. Viral mimicry of cytokines, chemokines and their receptors Decoy receptors soak up the body’s cytokines, and fake cytokines redirect the response in the virus’s favour.56PubMed Central. Viral mechanisms of immune evasion
Tumours use the body’s own signals. Support cells around tumours release IL-6, IL-10 and TGF-beta.57PubMed Central. Stromal cells in the tumor microenvironment: accomplices of tumor progression? These weaken natural killer cells, limit killer T cells, and turn helpers into suppressors.58PubMed Central. Stromal cells in the tumor microenvironment: accomplices of tumor progression? The calming signals that end healthy inflammation can thus shield a cancer. Reversing that suppression is a goal of immunotherapy, and the engineered IL-2 described earlier is one attempt.