Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors
Abstract Background 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...
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BMC
2025-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02035-z |
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| author | Alejandro Diaz-Barreiro Dominique Talabot-Ayer Arnaud Huard Gea Cereghetti Jenna Tonacini Mike Maillasson Antonio Francés-Monerris Erwan Mortier Gaby Palmer |
| author_facet | Alejandro Diaz-Barreiro Dominique Talabot-Ayer Arnaud Huard Gea Cereghetti Jenna Tonacini Mike Maillasson Antonio Francés-Monerris Erwan Mortier Gaby Palmer |
| author_sort | Alejandro Diaz-Barreiro |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions Our 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. |
| format | Article |
| id | doaj-art-b838d9c568db445c860a8eb93eebd3b6 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-b838d9c568db445c860a8eb93eebd3b62025-01-26T12:44:56ZengBMCCell Communication and Signaling1478-811X2025-01-0123111610.1186/s12964-025-02035-zFull-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptorsAlejandro Diaz-Barreiro0Dominique Talabot-Ayer1Arnaud Huard2Gea Cereghetti3Jenna Tonacini4Mike Maillasson5Antonio Francés-Monerris6Erwan Mortier7Gaby Palmer8Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of GenevaDivision of Rheumatology, Department of Medicine, Faculty of Medicine, University of GenevaDivision of Rheumatology, Department of Medicine, Faculty of Medicine, University of GenevaDepartment of Chemistry, University of CambridgeDivision of Rheumatology, Department of Medicine, Faculty of Medicine, University of GenevaNantes Université, CNRS, InsermInstitut de Ciència Molecular, Universitat de ValènciaNantes Université, CNRS, InsermDivision of Rheumatology, Department of Medicine, Faculty of Medicine, University of GenevaAbstract Background 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. Methods 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. Results 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. Conclusions Our 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.https://doi.org/10.1186/s12964-025-02035-zCytokineInterleukin-1 familyInterleukin-38Receptor antagonist |
| spellingShingle | Alejandro Diaz-Barreiro Dominique Talabot-Ayer Arnaud Huard Gea Cereghetti Jenna Tonacini Mike Maillasson Antonio Francés-Monerris Erwan Mortier Gaby Palmer Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors Cell Communication and Signaling Cytokine Interleukin-1 family Interleukin-38 Receptor antagonist |
| title | Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors |
| title_full | Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors |
| title_fullStr | Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors |
| title_full_unstemmed | Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors |
| title_short | Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors |
| title_sort | full length and n terminally truncated recombinant interleukin 38 variants are similarly inefficient in antagonizing interleukin 36 and interleukin 1 receptors |
| topic | Cytokine Interleukin-1 family Interleukin-38 Receptor antagonist |
| url | https://doi.org/10.1186/s12964-025-02035-z |
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