The family of interleukin-17 (IL-17) includes six molecules that respond to infection, in addition to participating in various physiological and pathological processes. A new paper in Signal Transduction and Targeted Therapy reviews the multifunctional role of IL-17 in the body.
Study: The IL-17 family in diseases: from bench to bedside. Image Credit: Schira / Shutterstock.com
Introduction
IL-17 comprises IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F, all of which have related structures. IL-17A, also known as cytotoxic T-lymphocyte-associated antigen 8 (CTLA-8), has been widely studied.
There are five receptor subunits that are assembled to form different receptor types. With diverse receptors and ligands, the IL-17 signaling family performs multiple functions.
IL-17 is expressed primarily by a subset of CD4+ T helper cells (Th17). IL-17 is also produced by natural killer (NK) cells, CD8+ T-cells, dendritic cells, macrophages, and neutrophils during infection.
CD4+ and CD8+ T-cells produce IL-17 in response to T-cell receptor (TCR) activation. Comparatively, innate immune cells produce IL-17 in response to other pro-inflammatory cytokines, especially IL-1 and IL-23.
IL-17 binds to its receptor, IL-17R, through the adapter molecule Act1, which activates downstream pathways. These involve tumor necrosis factor (TNF) receptor-associated factors (TRAFs) and E3 ligase-mediated ribonucleic acid (RNA) binding that induces transcription and post-transcriptional gene activation.
Direct pro-inflammatory effects
IL-17 signaling mediates transcriptional signaling and feedback. IL-17 enhances the inflammatory response by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, thereby leading to the transcription of target messenger RNA (mRNA).
IL-17 is regulated by feedback, which prevents an overly prolonged or hyperactive inflammatory response.
Another mode by which multiple genes in the IL-17 pathways are regulated is through the stability of the mRNA transcript. For example, both MAPK and NF-κB pathways produce mRNA with an unstable 3’ untranslated region (UTR) to which RNA-binding proteins (RBP) such as Act1 can bind, thus enhancing stability, which promotes its translation to inflammatory cytokines. Conversely, another RBP known as ribonuclease regnase-1 promotes its breakdown.
For IL-17, the unique positive and negative feedback regulatory mechanisms of the signaling pathway render it a moderate signaling activator compared to other inflammatory stimuli.”
Future drugs could be developed to antagonize RBPs specific to certain autoimmune diseases or competitively bind to target mRNA.
Synergistic effects
IL-17 acts with other inflammatory signaling molecules, such as gamma-interferon (IFNγ), IL-13, and transforming growth factor-beta (TGF-β). Conversely, IL-17 pairs with other non-inflammatory cytokines like epidermal growth factor receptor (EGFR), fibroblast growth factor 2 (FGF2), CARD14, or NOTCH to promote tissue repair, cancer, and autoimmune disease.
CARD14 is raised in psoriasis and acts to enhance skin inflammation induced by IL-17. Thus, IL-17 inhibitors are effective in treating this condition.
Physiological roles
IL-17 increases neutrophil differentiation by producing granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1), and CXC chemokines by its target cells. Furthermore, IL-17 promotes antimicrobial responses, including bronchus-associated lymphoid tissue (BALT) defenses to tuberculosis bacilli, immunity against yeasts, and staphylococcal skin infections.
IL-17 promotes bacterial killing by innate immune cells, prevents mucosal colonization, and strengthens cellular defenses against intracellular pathogens.
Th17 cells are induced by multiple viruses, including influenza, West Nile, and adenovirus. However, the human immunodeficiency virus (HIV) selectively depletes memory Th17 cells, thereby reducing their number and producing a Th1 response. By shaping a predominantly regulatory T-cell (Treg) profile, the disease progresses to immunodeficiency.
IL-17 stimulates macrophage activity and neutrophil recruitment, protecting against mainly intracellular parasitic infections. It also promotes inflammatory granulomas and fibrotic sequelae following infection with liver flukes, for instance.
IL-17 may worsen the outcome with viruses like dengue, hepatitis B (HBV), HCV, and gamma herpes virus by exacerbating viral injury. Thus, IL-17 has protective and pathogenic effects during some infections.
In the coronavirus disease 2019 (COVID-19), IL-17 was associated with a cytokine storm leading to acute respiratory distress syndrome (ARDS) and critical disease.
IL-17 also helps build a tight epithelial barrier in the skin and intestine, thereby maintaining tight junctions, increasing the production of antibacterial defense molecules, and activating stem cells to repair damaged sites. IL-17 also promotes bone stability and healing by activating osteoblasts.
Pathologic roles of IL-17
IL-17 remains at stable low levels under normal conditions; however, it can cause malignant transformation and autoimmune phenomena if chronically raised. IL-17 is raised in psoriasis, psoriatic arthropathy, and ankylosing spondylitis as it is released from Th17 cells, neutrophils, and CD8+ cells.
IL-17 levels are high in individuals with inflammatory bowel disease. The use of IL-17 blockers is not associated with worsening or new-onset of these conditions.
IL-17 levels are raised in systemic lupus erythematosus (SLE) but without any direct association with severity or symptoms. The real association may be with other Th17 cell cytokines like IL-21 and IL-22 and may be indirectly associated with IL-17. IL-23 promotes Th17 cell differentiation and proliferation, and monoclonal anti-IL-23 antibodies have shown promise in the treatment of active SLE.
Due to the skewed Th17/Treg ratio in SLE, restoring the proportion of Treg cells may modulate inflammation and reduce the severity of this disease. Other therapeutic possibilities include antagonists of IL-17-promoting activated B-cells, monocytes, and plasmacytoid dendritic cells, a subset of which produce anti-double-strand DNA antibodies.
Experimental autoimmune encephalomyelitis (EAE) has been traced in part to IL-17 activity. In a pilot study, patients with multiple sclerosis (MS) showed impressive responses to the use of secukinumab, an IL-17 antagonist; however, further studies are needed to confirm this effect.
IL-17 in cancer
Chronically raised IL-17 levels in prolonged inflammation may predispose individuals to cancer by enhancing the rate of mutations and precancerous cell change. IL-17 also promotes tumor progression by increasing the rate of cell proliferation and metastasis, along with immune tolerance in transformed cells. This is supported by the observation of unusually high IL-17 levels in the tumor microenvironment.
IL-17 may have both pro- and anti-tumorigenic characteristics in the same type of cancer.”
IL-17 inhibitors in autoimmune disease
Given the role of IL-17 in many autoimmune diseases (AIDs) such as psoriasis, psoriatic arthropathy, and SLE, monoclonal antibodies (mAbs) to IL-17 have been studied in pursuit of effective therapies. Two pathways have been used, including direct anti-IL-17 antagonists and indirect blockade by inhibiting Th17 cell differentiation.
Some direct anti-IL-17 antagonists include mAbs like secukinumab, ixekizumab, and brodalumab, all approved by the United States Food and Drug Administration (FDA) for psoriasis. These agents target IL-17A, all IL-17 cytokines, and IL-17A, respectively.
IL-17 in cancer management
IL-17 can promote tumor development and progression, as well as tumor regression. Anti-IL-17C blockade may help lung cancer patients by preventing the emergence of resistance to anti-programmed cell death protein 1 (PD-1) immunotherapy. Other studies showed promising results when using IL-17 as a marker for cancer therapy targeting IL-17-bearing cancer stem cells.
What are the implications?
IL-17 is a key molecule in multiple physiological and pathological pathways. Currently, several mAbs are available to abrogate this pathway; however, their cost, inconvenience, and immunosuppression are notable disadvantages. Oral small molecule drugs (SMDs) would be preferable, as they have shorter durations of action, are cost-effective, and are easy to use.
The primary caution while using IL-17 blockade is the need to preserve host immune function. Further research may help provide better therapies for autoimmune and malignant conditions.
Journal reference:
- Huangfu, L., Li, R., Huang, Y., & Wang, S. (2023). The IL-17 family in diseases: from bench to bedside. Signal Transduction and Targeted Therapy. doi:10.1038/s41392-023-01620-3.
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