Recombinant human IL-25 (IL-17E) protein - Bioactive cytokine

IL-25 background

Interleukin 17 (IL-17) is a family of six closely related cytokines (IL-17A to IL-17F) that exhibit both pro- and anti-inflammatory activity. IL-25 (also known as IL-17E) is primarily described as a "barrier surface" cytokine. It is produced by various cell types, including T helper 2 (Th2) cells, mast cells, or epithelial cells, and it acts on both immune and tissue-resident cells in barrier tissues (e.g., skin, lungs, gastrointestinal tract) [1, 2].

IL-25 binds a homodimeric transmembrane receptor that comprises the IL-17RA subunit shared by all IL-17 isoform receptors and the IL-17RB subunit. The binding of IL-25 to its receptor triggers the recruitment of ACT1 (activator of NF-κB1), which recruits and ubiquitinates TRAF6 (TNF receptor-associated factor 6). The subsequent signaling cascade leads to the activation of the canonical NF-κB and AP-1 pathways [1, 2]. While all IL-17 family members promote inflammatory neutrophilic responses, IL-25 induces the expression of type 2 cytokines (i.e., IL-4, IL-5, IL-13, and TSLP). This functional divergence led to the renaming of IL-17E as IL-25 [2].

Relevance for therapeutics development

Dysregulated IL-25 expression has been associated with multiple inflammatory disorders.

• In the skin, IL-25 contributes to epidermal homeostasis under steady state conditions [1]. However, elevated IL-25 expression is found in the lesions of skin disorders, such as atopic dermatitis, psoriasis, and contact dermatitis [1].
• In the gut, IL-25 expression by chemosensory cells is upregulated upon parasite infection. IL-25 then contributes to recruiting Th2 cells and ILC2 (type 2 innate lymphoid cells) to mediate anti-helminth immunity [1]. IL-25 has been reported to play both pathogenic and protective functions in different inflammatory bowel disease (IBD) settings, which is characterized by an imbalance of the Th1/Th2 cytokine response. Although extensive data have been generated in experimental colitis models, the precise role of IL-25 in ulcerative colitis patients remains incompletely defined [1].
• In the airways, IL-25 expression by chemosensory cells is induced in response to infections and allergens. While IL-25 may contribute to epithelial protection, sustained type-2 immune activation has been implicated in the pathogenesis of chronic rhinosinusitis and asthma [1].

Given its central role in type-2 immunity, therapeutic blockade of IL-25 signaling represents a promising strategy to alleviate Th2-driven inflammatory diseases. SM17, a humanized monoclonal antibody targeting the IL-17RB subunit of the IL-25 receptor, has completed a phase I clinical trial (NCT05332834), demonstrating a favorable safety, tolerability, and pharmacokinetic profile. Further clinical development is ongoing for the treatment of atopic dermatitis. In preclinical mouse models, administration of IL-25-blocking antibodies has been shown to ameliorate Th2-mediated airway inflammation [1].

​References:

1. Borowczyk, J., et al., 2021. IL-25 (IL-17E) in epithelial immunology and pathophysiology. Journal of Allergy and Clinical Immunology. 148(1):40-52.
2. McGeachy, M.J. et al., 2019. The IL-17 Family of Cytokines in Health and Disease. Immunity. 50(4):892-906.