Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors
SUMMARY
Interleukin (IL)-38 is an IL-1 family cytokine that was proposed to exert anti-inflammatory effects. However, its mechanisms of action are not well understood and the identity of the IL-38 receptor(s) remains debated. Proposed candidates include the IL-1 receptor (IL-1R1), the IL-36 receptor (IL-36R) and the orphan receptor IL-1RAPL1. Yet, in literature, IL-38 is often presented as an IL-36R antagonist.
The N-terminus of the IL-38 protein produced in a human keratinocyte cell line and of endogenous epidermal IL-38 isolated from healthy human skin was characterized by mass spectrometry. The effects of various recombinant forms of IL-38 on IL-36R- and IL-1R1-mediated responses were assessed in IL-36R HEK Blue reporter cells and in a normal human keratinocyte cell line. IL-8 and IL-6 production was quantified by ELISA. Binding of recombinant IL-38 proteins to the IL-36R was assessed by surface plasmon resonance.
Analysis of its native N-terminus revealed that the IL-38 protein produced by human keratinocytes starts at cysteine 2. In cell-based assays, neither full-length amino acid 2-152 IL-38 nor two N-terminally truncated forms of the protein showed efficient antagonist activity on IL-36R- and IL-1R1-mediated responses. The recombinant IL-38 proteins bound to the IL-36R with only moderate affinity, which may provide a mechanistic explanation for inefficient IL-36R antagonism.
These results argue against meaningful inhibitory effects of any of the recombinant IL-38 variants tested on IL-36R or IL-1R1-mediated responses. The mechanisms underlying reported anti-inflammatory effects of IL-38 are thus still unclear, but seem unlikely to be mediated by classical IL-36R or IL-1R1 antagonism.
Full article: https://doi.org/10.1186/s12964-025-02035-z
Why is it Important?
After the discovery of interleukin (IL)-38 in 2001, early studies suggested that it might act as an anti-inflammatory IL-1 or IL-36 receptor antagonist. However, over two decades of in vitro and in vivo studies revealed that its biology is far more intricate. The effects of IL-38 can be both anti- and pro-inflammatory, and its broad anti-inflammatory activity distinguishes it from the natural IL-1 and IL-36 receptor antagonists, which target only their specific receptors. Nevertheless, the prevailing assumption remains that IL-38 is simply another IL-36 receptor antagonist.
This study challenges this misconception by taking a systematic approach to investigate the effects of IL-38 on specific, molecularly defined responses, in well-controlled experimental systems. These findings will hopefully encourage further in-depth investigations into the role of IL-38 and its mechanisms of action, which could open new therapeutic avenues for chronic inflammatory diseases such as psoriasis.