Interleukin-6 (IL-6) is a signaling protein your immune system uses to coordinate its response to injury and infection. It belongs to a class of molecules called cytokines, which act as chemical messengers between cells. What makes IL-6 unusual is its dual nature: it can both ramp up inflammation when your body is under threat and help dial it back down once the job is done. In healthy people, blood levels of IL-6 typically fall below about 5 pg/mL, but during illness or intense exercise, those levels can spike dramatically.
How IL-6 Works in the Body
When you get an infection or injury, immune cells at the site release IL-6 into the bloodstream as an early alarm signal. The main producers are monocytes, macrophages, and T cells, though epithelial cells and certain connective tissue cells called fibroblasts can also release it. Two other inflammatory signals, IL-1 and TNF-alpha, are the primary triggers that tell these cells to start pumping out IL-6. Think of it as a relay: the first responders at a wound or infection site send out IL-1 and TNF-alpha, which then amplify the response by prompting a wave of IL-6.
Once IL-6 enters the bloodstream, it travels to the liver and triggers the production of what are known as acute phase proteins. The most familiar of these is C-reactive protein (CRP), a marker doctors commonly test for when checking for inflammation. IL-6 also stimulates production of serum amyloid A and fibrinogen, a protein involved in blood clotting. This is one reason your CRP level rises when you’re sick: IL-6 is telling your liver to flood the blood with protective proteins.
Beyond the liver, IL-6 shapes the broader immune response. It helps activate a type of white blood cell called T helper cells, influences B cells to mature and produce antibodies, and plays a role in blood cell formation. It also reaches the brain, where it can act on the hypothalamus to trigger fever. The likely mechanism involves stimulating the production of prostaglandins at the blood-brain barrier, which then shift the brain’s temperature set point upward. So when you develop a fever during an infection, IL-6 is one of the key molecules making that happen.
IL-6 as a Muscle Hormone During Exercise
IL-6 isn’t just about illness. Working skeletal muscle produces large amounts of it during physical activity, and in this context it behaves more like a hormone than an inflammatory signal. The amount released depends on how hard and how long you exercise, and it increases further when your muscles are low on stored glycogen (their primary fuel).
During prolonged exercise, muscle-derived IL-6 enters the bloodstream and travels to the liver, where it stimulates glucose production to keep blood sugar stable while your muscles are burning through fuel at a high rate. It also acts on fat tissue to promote lipolysis, the breakdown of stored fat into free fatty acids that can be used for energy. This dual action on the liver and fat tissue helps explain how exercise supports both blood sugar regulation and fat burning. Studies using IL-6 infusions in humans have confirmed that it increases hepatic glucose output and raises circulating free fatty acid levels in a dose-dependent way.
When IL-6 Levels Go Wrong
Problems arise when IL-6 production becomes excessive or chronic. In rheumatoid arthritis, persistently high IL-6 drives ongoing joint inflammation and tissue damage. In a rare condition called Castleman disease, IL-6 overproduction causes widespread lymph node swelling and systemic symptoms. And in certain acute crises, IL-6 plays a central role in what’s known as cytokine storm, a dangerous feedback loop where the immune system floods the body with inflammatory signals faster than it can control them.
Cytokine storms can occur in several settings. They are a hallmark of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), both of which involve runaway immune activation. They also occur as cytokine release syndrome (CRS) after certain cancer immunotherapies, particularly CAR T-cell therapy. During the COVID-19 pandemic, severely ill patients often showed dramatically elevated IL-6, which contributed to the lung damage and organ failure seen in the worst cases.
IL-6 as a Diagnostic Marker
Because IL-6 rises quickly at the onset of infection, it has value as an early warning biomarker. A 2020 meta-analysis pooling data from a large number of studies found that healthy adults have an average IL-6 level of about 5.2 pg/mL, with values rising by roughly 0.05 pg/mL for each year of age. When levels climb well above that baseline, it signals that significant inflammation is underway.
One area where IL-6 testing shows particular promise is in detecting late-onset sepsis in newborns. A recent systematic review and meta-analysis found that IL-6 had a pooled sensitivity of 85.2% and specificity of 84.1% for this diagnosis, with an overall diagnostic accuracy rating of excellent. A positive IL-6 result raised the probability of neonatal sepsis to about 67%, while a negative result dropped it to just 6%. The main challenge is that different hospitals and labs use different cutoff values, which affects how reliably the test performs across settings.
Medications That Block IL-6
Given IL-6’s role in driving inflammatory disease, blocking its activity has become a successful treatment strategy. Two medications that target the IL-6 receptor are currently approved in the United States and Europe: tocilizumab and sarilumab. Both work by attaching to the IL-6 receptor on cell surfaces, preventing IL-6 from binding and delivering its inflammatory signal.
Both drugs are approved for moderate to severe rheumatoid arthritis in patients who haven’t responded well to other treatments. They can be used either alongside other rheumatoid arthritis medications or on their own. Tocilizumab has also been approved for additional conditions, including giant cell arteritis, a type of blood vessel inflammation, and cytokine release syndrome triggered by CAR T-cell cancer therapy. During the pandemic, it was authorized for hospitalized COVID-19 patients with severe inflammation. These medications carry risks related to suppressing immune function, including increased susceptibility to infections, but they have demonstrated strong efficacy and tolerability in clinical use.
The Dual Nature of IL-6
What makes IL-6 so interesting, and so tricky to manage medically, is that the same molecule can be protective or destructive depending on context. When your muscles release it during a workout, it helps regulate energy and may contribute to the anti-inflammatory benefits of regular exercise. When it surges briefly during an acute infection, it orchestrates a necessary defense. But when production spirals out of control or persists for months or years, it drives tissue damage, chronic disease, and in extreme cases, life-threatening immune crises. Understanding which role IL-6 is playing in a given situation is what allows doctors to decide when blocking it will help and when the body’s natural IL-6 response should be left to do its job.