Interleukin-17C (IL-17C) is a specific signaling protein, known as a cytokine, that plays a significant role in the body’s immune system. It functions as a messenger, allowing cells to communicate and coordinate various responses. IL-17C is one of six known members of the Interleukin-17 (IL-17) family of cytokines, which also includes IL-17A, IL-17B, IL-17D, IL-17E, and IL-17F. While part of this larger family, IL-17C possesses distinct characteristics and functions that set it apart.
Cellular Origins and Triggers
IL-17C is primarily produced by epithelial cells, which form the protective linings of various body surfaces, including the skin, gut, and lungs. These cells act as a continuous surveillance system at the body’s external barriers, detecting potential threats. Unlike some other immune molecules generated by mobile immune cells, IL-17C’s origin largely stems from these stationary protective layers, highlighting its localized action.
The release of IL-17C is initiated by specific signals that indicate a breach or challenge to these barrier tissues, such as infections or injuries. For instance, components of bacteria and fungi, recognized by receptors such as Toll-like receptor 2 (TLR2) and Toll-like receptor 5 (TLR5), can stimulate IL-17C production. Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) and Tumor Necrosis Factor alpha (TNF-α) also act as potent inducers of its release. Mechanical or physical stress to the epithelial tissue can also prompt these cells to generate IL-17C, signaling a need for local immune activation.
IL-17C expression can be significantly upregulated at the very early stages of certain disease processes, highlighting its role in initial immune responses. Its receptor, a complex of IL-17RA and IL-17RE, is notably expressed on epithelial cells themselves, allowing for a self-reinforcing loop. This means that once secreted, IL-17C can also act back on the epithelial cells to further amplify their protective responses.
Role in Immune Defense
In a healthy context, IL-17C contributes to the body’s innate immune defense, particularly at barrier surfaces, where it plays a crucial role. It helps to maintain the integrity and function of these protective layers, acting as a local chemical messenger within the epithelial tissue itself. This action reinforces the body’s initial physical and chemical barriers, which are designed to prevent pathogen entry and establish early control over infections.
IL-17C functions as a signal to recruit other immune cells to the site of potential infection or damage. It effectively acts as a localized alert, guiding immune responders, especially neutrophils, to the affected area. Neutrophils are a type of white blood cell that specialize in engulfing and destroying invading microorganisms. This targeted recruitment facilitates a rapid response to contain and eliminate threats before they can spread further into deeper tissues, thereby protecting the host.
Furthermore, IL-17C promotes the production of various other immune-supporting molecules, including additional cytokines and a range of antimicrobial peptides. These peptides directly combat pathogens such as bacteria and fungi, while the cytokines help to coordinate a broader immune response. Studies have shown that IL-17C is important for early mucosal responses to specific bacterial infections, like Citrobacter rodentium, in the gastrointestinal tract. In these scenarios, IL-17C has been observed to synergize with other immune molecules, such as IL-22, to enhance the production of antimicrobial peptides, which are crucial for host defense. Signaling through its receptor complex (IL-17RA/IL-17RE) and a molecule called Act1, IL-17C activates specific cellular pathways, including NF-κB and MAPK, which are involved in turning on genes for these protective responses.
Involvement in Inflammatory Diseases
While IL-17C plays a beneficial role in protecting the body, its system can become overactive or dysregulated, leading to persistent inflammation and contributing to disease. Unlike a controlled, temporary inflammatory response that resolves after a threat is neutralized, chronic inflammation is sustained, causing ongoing tissue damage. This prolonged presence of IL-17C can drive pathological processes in various inflammatory conditions.
IL-17C is notably implicated in autoimmune and inflammatory conditions, particularly psoriasis. In psoriatic skin lesions, IL-17C is found at higher levels compared to other IL-17 family members. Its excessive production in the skin contributes to the hallmark features of psoriasis, including the abnormal proliferation of skin cells and sustained inflammation. It stimulates keratinocytes, the predominant cells of the epidermis, to produce increased amounts of antimicrobial peptides, pro-inflammatory cytokines, and chemokines that attract neutrophils, thereby intensifying the inflammatory cycle characteristic of psoriasis.
Beyond skin conditions, IL-17C also contributes to inflammatory bowel disease (IBD), where its dysregulation can exacerbate intestinal inflammation and impair the gut’s barrier function. The sustained inflammatory signals perpetuated by IL-17C contribute to the ongoing damage observed in the intestinal lining of individuals with IBD. In some contexts, IL-17C can even play dual roles, showing potential to both attenuate inflammation in conditions like colitis while increasing it in others such as psoriasis or experimental autoimmune encephalomyelitis (EAE). For instance, mice lacking IL-17C have shown partial resistance to EAE, suggesting its contribution to the disease’s progression.
Therapeutic Implications
The growing understanding of IL-17C’s involvement in driving chronic inflammatory diseases has opened new avenues for targeted drug development. Since its dysregulated activity contributes to conditions like psoriasis and inflammatory bowel disease, blocking its action presents a promising therapeutic strategy. This approach involves developing specific medications designed to neutralize or interfere with IL-17C’s signaling pathways.
These targeted therapies, often referred to as biologic drugs, aim to precisely block the IL-17C protein itself or its receptor, thereby reducing the excessive inflammation it promotes. By specifically targeting IL-17C, these treatments seek to restore a more balanced immune response without broadly suppressing the entire immune system. This offers the potential for more focused and effective treatment options for patients suffering from chronic inflammatory conditions.
Research is actively underway to develop new therapeutic agents that can modulate IL-17C activity. Clinical trials are in progress to assess the effectiveness and safety of neutralizing IL-17C in patients with immune-mediated diseases. This ongoing scientific effort aims to translate the detailed understanding of IL-17C’s biology into practical, novel treatments, ultimately improving outcomes for individuals affected by these debilitating conditions.