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Thirteen years to get from b to a: one of the neglected isoforms of IL-37 enters the stage

Cellular & Molecular Immunology volume 21, pages 201–202 (2024)Cite this article

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Interleukin (IL)-37 is one of the few anti-inflammatory members of the predominantly pro-inflammatory IL-1 cytokine family. IL-37 possesses alarmin-like properties [1] and exerts its activities via intracellular [2] as well as cell surface receptor-dependent mechanisms, and the latter involves IL-1R8 and IL-18Rα [3]. Because of its powerful and broad-spectrum “peacemaking” [4] functions, considerable efforts have been invested in developing IL-37-based anti-inflammatory therapeutics [5, 6]. A thorough understanding of IL-37’s mechanisms of action and its role in various inflammatory diseases is a pivotal aspect of such efforts [6], particularly in view of a recent study suggesting that IL-37 may have pro-inflammatory activity under certain circumstances [7]. The study by Wei et al. in the current issue of Cellular and Molecular Immunology provides new insights in this field.

IL-37 has five known isoforms, termed IL-37a–e. IL-37b, the longest isoform that contains 5 of the 6 exons, has almost exclusively enjoyed the limelight, whereas the activities and mechanisms of action of the other isoforms remain largely unknown. Wei et al. [8] focused on the anti-inflammatory functions of IL-37a, the only isoform utilizing exon 3 at the non-core-structure-forming part of the N-terminus [9]. They demonstrated that IL-37a not only has extracellular functions dependent on IL-1R8 but also acts as a nuclear factor via IL-1R8-independent mechanisms [8]. The authors report that these nuclear functions include increasing peroxisome proliferator-activated receptor-γ (Pparg) expression and are predominantly utilized by full-length (FL)-IL-37a (amino acids (AA)1–192) and, interestingly, also by an N-terminal fragment termed N-IL-37a (AA1–21). In contrast, the anti-inflammatory activities of a protein the authors call mature (m)IL-37a (AA22–192; note: this abbreviation must not be confused to mean mouse IL-37, which remains unidentified) were more dependent on IL-1R8. The authors suggest that elastase might generate mIL-37a and N-IL-37a by cleaving FL-IL-37a at the putative site L21-R22.

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Authors and Affiliations

  1. Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia

    Steven X. Cho, Ina Rudloff, Claudia A. Nold-Petry & Marcel F. Nold

  2. Department of Pediatrics, Monash University, Melbourne, VIC, Australia

    Steven X. Cho, Ina Rudloff, Claudia A. Nold-Petry & Marcel F. Nold

  3. Cancer Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia

    Andrew M. Ellisdon

  4. Monash Newborn, Monash Children’s Hospital, Melbourne, VIC, Australia

    Marcel F. Nold

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  1. Steven X. Cho
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Correspondence to Marcel F. Nold.

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Competing interests

AME, CANP, and MFN hold patents on the therapeutic use of IL-37.

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Cho, S.X., Rudloff, I., Ellisdon, A.M. et al. Thirteen years to get from b to a: one of the neglected isoforms of IL-37 enters the stage. Cell Mol Immunol 21, 201–202 (2024). https://doi.org/10.1038/s41423-023-01111-z

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