What Is IL-17? Its Role in Immunity and Disease

Interleukin-17, or IL-17, is a family of six signaling proteins (IL-17A through IL-17F) that act as chemical messengers between immune cells and the tissues they protect. IL-17A, the founding and most studied member, is best known for rallying the body’s first-responder defenses against bacteria and fungi at surfaces like the skin, mouth, and gut lining. But the same inflammatory power that fights infection can, when misdirected or chronic, drive diseases ranging from psoriasis to joint inflammation to cardiovascular damage. That tension between protection and pathology is what makes IL-17 one of the most actively researched molecules in modern immunology.

Six Cytokines, Not Just One

When researchers say “IL-17,” they usually mean IL-17A, the molecule discovered first and targeted by most current drugs. The full family, though, contains six members labeled A through F, each encoded by a separate gene but sharing a similar three-dimensional shape built around a structural motif resembling a knot of chemical bonds also found in certain nerve growth factors.¹ IL-17A and IL-17F are the closest relatives and overlap in function, while other family members like IL-17E (also called IL-25) have quite different jobs, such as promoting allergic-type responses rather than the neutrophil-heavy inflammation typical of IL-17A.²

The receptors that pick up IL-17 signals are also distinctive. IL-17RA, the main receptor, has structural features that set the whole family apart from other cytokine systems.³ When IL-17A binds to its receptor, the signal passes through an adaptor protein called Act1, which connects to downstream machinery that ultimately switches on genes for inflammation and antimicrobial defense.⁴ The practical upshot is that cells lining your skin, lungs, and gut receive IL-17 signals and respond by producing their own alarm chemicals and germ-killing peptides, rapidly scaling up the local inflammatory response.

Defending Body Surfaces Against Infection

IL-17’s primary job is protecting the body’s barrier tissues, the surfaces constantly exposed to the outside world. When bacteria or fungi breach the skin or a mucous membrane, IL-17A prompts nearby cells to release chemokines that recruit neutrophils, the immune system’s most abundant rapid-response cells. It also stimulates production of antimicrobial peptides and helps maintain the physical integrity of the epithelial barrier itself.⁵

The clearest evidence of IL-17’s importance comes from people and animals that lack it. Mice deficient in IL-17 signaling show broad vulnerability to infections across different mucosal surfaces. In humans, rare genetic conditions that impair IL-17A, IL-17F, or their receptor lead to chronic mucocutaneous candidiasis, a persistent fungal infection of the skin, nails, and mouth caused by Candida albicans.⁶ IL-17A also plays a role in vaccine-driven immunity. In one mouse study, knocking out IL-17A completely abolished the protective effect of vaccination against Staphylococcus aureus and Candida albicans.⁷ These findings paint IL-17 as a linchpin of mucosal immunity, especially against fungal pathogens.

Why IL-17 Rarely Acts Alone

One of IL-17A’s distinctive traits is that its inflammatory effect becomes dramatically stronger in combination with other cytokines. On its own, IL-17A produces a modest response in many cell types. Pair it with tumor necrosis factor (TNF), however, and the result is far greater than either signal alone. In synovial fibroblasts from patients with rheumatoid arthritis and osteoarthritis, IL-17A or TNF alone barely moved the needle on certain inflammatory genes, but the combination produced a strong spike in expression.⁸ A similar pattern appears in skin. A screening of 36 cytokines on keratinocytes found that IL-17A, IL-22, oncostatin M, TNF-α, and IL-1α together synergistically ramped up the production of immune-recruiting and antimicrobial factors far beyond what any individual cytokine achieved.⁹

This synergy matters clinically. It explains why diseases driven by IL-17 often also involve TNF and why combination therapy or targeted selection of which cytokine to block can produce strikingly different outcomes.

Psoriasis and the IL-17 Feed-Forward Loop

Psoriasis is the disease where IL-17’s role is understood most thoroughly and where blocking it has produced some of the most impressive results. In psoriatic skin, multiple IL-17 family members, including IL-17A, IL-17C, and IL-17F, act on keratinocytes, endothelial cells, and immune cells to stimulate the runaway skin thickening and inflammation characteristic of plaques.¹⁰ IL-17A accelerates keratinocyte proliferation, and keratinocytes in turn release more chemokines that attract IL-17-producing immune cells back to the skin, creating a self-reinforcing cycle of inflammation.¹¹ Breaking that cycle with antibodies that neutralize IL-17A has proven highly effective. Several monoclonal antibodies now target either IL-17A directly (secukinumab, ixekizumab), both IL-17A and IL-17F simultaneously (bimekizumab), or the IL-17 receptor (brodalumab).¹²

Joint Disease and Enthesitis

Beyond skin, IL-17A is a key player in certain forms of inflammatory joint disease, particularly axial spondyloarthritis and psoriatic arthritis. In spondyloarthritis, a hallmark early lesion is enthesitis, inflammation where tendons and ligaments attach to bone. Researchers have identified resident immune cell populations at the human enthesis that can produce IL-17A locally, and the cytokine appears to amplify the inflammation by inducing other signaling molecules from the surrounding tissue cells.¹³ Adding complexity, IL-17A seems to have a dual role in bone: it may promote erosion at some sites while simultaneously encouraging abnormal new bone formation at others. That paradox continues to generate debate in the rheumatology community.

The Gut Paradox

If IL-17 drives inflammation in the skin and joints, you might expect that blocking it would also help inflammatory bowel disease. The opposite turned out to be true, and the discovery was one of the bigger surprises in recent cytokine biology. Clinical trials found that while blocking the shared IL-12/IL-23 pathway helps Crohn’s disease, directly inhibiting IL-17A or its receptor actually made Crohn’s disease worse. In preclinical models, inhibiting IL-17A or its receptor severely weakened the intestinal epithelial barrier, leading to increased colonic inflammation and accelerated death.¹⁴

The explanation is that IL-17A, in the gut specifically, acts directly on epithelial cells to help maintain barrier function. Knock it out and the barrier weakens, allowing bacteria to cross into the tissue and provoke even worse inflammation than before. This is a vivid example of how the same cytokine can be destructive in one organ and protective in another, and it has real consequences for drug development: IL-17 blockers carry warnings about use in patients with active inflammatory bowel disease.

Multiple Sclerosis and the Blood-Brain Barrier

IL-17A is also implicated in multiple sclerosis (MS), an autoimmune condition where the immune system attacks the insulating coating of nerve fibers. Endothelial cells forming the blood-brain barrier carry receptors for IL-17 and IL-22, and exposure to these cytokines disrupts the tight junctions that normally keep blood-borne immune cells out of the brain.¹⁵ In patients with relapsing-remitting MS, IL-17A levels in the cerebrospinal fluid correlated with a standard marker of blood-brain barrier leakiness, and lab experiments showed that IL-17A reduced the expression of genes responsible for maintaining tight junctions in barrier cells.¹⁶ Blocking IL-17A (but not IL-17F) attenuated the MS-like disease in animal models, suggesting IL-17A specifically is the problematic family member in the central nervous system.

Cardiovascular Inflammation

Research increasingly connects IL-17 to heart and blood vessel disease, expanding the cytokine’s relevance well beyond traditionally “immune” conditions. Preclinical evidence shows IL-17’s pro-inflammatory effects contributing to atherosclerosis, high blood pressure, and adverse outcomes after heart attacks, primarily through endothelial dysfunction, immune cell infiltration into vessel walls, and oxidative stress. Elevated IL-17 levels correlate with vulnerable plaque burden, worse cardiac events, and the severity of hypertension.¹⁷

In a mouse model where IL-17A was overexpressed specifically in skin cells, the animals developed not only severe psoriasis-like skin inflammation but also increased blood pressure, left ventricular hypertrophy, and reduced survival compared to controls. The damage was linked to increased production of reactive oxygen species in blood vessels and infiltration of inflammatory cells into the vascular wall.¹⁸ Findings like this have raised the question of whether the well-documented cardiovascular risk associated with chronic inflammatory skin disease is partly IL-17-mediated, and whether IL-17-blocking therapies might offer cardiovascular protection as a side benefit.

The Dual Face of IL-17 in Cancer

IL-17’s relationship with cancer is genuinely contradictory, and researchers have not yet resolved the tension. During the early stages of tumor development, IL-17 signaling can promote tumor cell proliferation. Yet in certain transplant-based tumor models, IL-17 has shown antitumor effects. The outcome depends on the type of IL-17, the stage of the cancer, and where in the body the tumor is growing.¹⁹ Studies using adoptive T-cell therapy have found that IL-17-producing T cells can be anti-tumorigenic, but mice lacking key IL-17-pathway genes show evidence that these cells can also promote tumor growth in other settings.²⁰ The upshot for now is that no one should assume IL-17 blockers either raise or lower cancer risk as a straightforward rule. The picture depends heavily on context, and clinical data on long-term cancer incidence in patients on IL-17 inhibitors is still accumulating.

Candidiasis Risk When IL-17 Is Blocked

Given that IL-17 is essential for fighting Candida at mucosal surfaces, it is unsurprising that drugs blocking the pathway carry an increased risk of yeast infections. Clinical trials and observational data consistently show a higher incidence of candidiasis in patients treated with IL-17 inhibitors.²¹ The risk is not uniform across all drugs in the class. Brodalumab and bimekizumab appear to pose a greater risk than secukinumab, while data on ixekizumab remain mixed. Higher doses and longer treatment duration further increase the risk.²² Most infections are mild oral or genital candidiasis that responds well to standard antifungal treatment, but the pattern neatly mirrors what geneticists observe in humans who are born without functional IL-17 signaling.

Wound Healing and Tissue Repair

IL-17 is not purely destructive. Recent work has revealed a constructive side: it helps injured epithelial tissue heal. After wounding, a specific subset of immune cells in the tissue releases IL-17A, which activates a metabolic switch in the cells at the wound edge. Those cells shift toward glycolysis, a fast energy-production pathway, through activation of the oxygen-sensing transcription factor HIF1α. This metabolic reprogramming is what allows the wound-front cells to migrate and close the gap. Blocking IL-17 signaling in the epithelium, or blocking HIF1α or glycolysis, derailed the repair process.²³ This finding reframes IL-17 not just as an inflammatory alarm signal but as a coordinator of the metabolic changes tissue needs to recover after damage.

Helping B Cells Make Antibodies

IL-17-producing T cells also interact meaningfully with B cells, the branch of the immune system responsible for producing antibodies. These T cells can drive B cells to proliferate strongly and to undergo class switch recombination, the process by which B cells change the type of antibody they produce to better suit the threat. Transferring IL-17-producing T cells into mice triggered the formation of germinal centers, the lymph node structures where high-quality antibody responses are refined, and promoted switching toward specific antibody subtypes. Blocking IL-17 signaling reduced both the number and size of those germinal centers.²⁴ This B-cell-helper function may be part of how IL-17 contributes to autoimmune diseases in which pathogenic autoantibodies are central to the damage, such as rheumatoid arthritis and lupus.

Environmental Influences on IL-17 Production

The amount of IL-17 your body produces is not fixed; it responds to environmental cues. One of the clearest examples is dietary salt intake. In mice, a high-salt diet increased the frequency of IL-17A-producing cells in the lining of both the small and large intestines while simultaneously suppressing the activity of regulatory T cells, the immune cells that normally put the brakes on inflammation.²⁵ In the same study, the high-salt diet worsened experimentally induced colitis. While mouse diet studies do not translate one-to-one to humans, findings like these feed into a broader body of work suggesting that modern Western diets, rich in sodium, may tilt the immune system toward a more inflammatory IL-17-heavy posture. That shift could, over time, raise the background risk for autoimmune and inflammatory conditions in predisposed individuals.

An Evolutionarily Ancient Molecule

IL-17 is not a recent invention of the mammalian immune system. Comparative genomic analyses have traced IL-17 family genes deep into the animal kingdom, with the earliest examples appearing in nematode worms such as Caenorhabditis elegans. The gene subsequently emerged in some mollusks and eventually diversified into the six-member family found in mammals today.²⁶ The fact that IL-17 predates the adaptive immune system itself hints that its original role was in innate barrier defense, the same function it still performs at mucosal surfaces today. Its later co-option into adaptive immunity, including its ability to help B cells and shape vaccine responses, represents a more recent evolutionary layering of new functions onto very old machinery.