No / Background  Interleukin (IL)-33 is a member of the IL-1 family and has been implicated in Th2-driven allergic diseases such as atopic dermatitis (AD) and asthma. The principal Th2 cytokine IL-4, found highly expressed in acute allergic eczema, is known to downregulate human β-defensin 2 (hBD2) expression in human keratinocytes and this is associated with superinfection in patients with AD. Objectives  To investigate the effect of IL-33 on the expression of hBD2 in human keratinocytes. Methods  hBD2 production by stimulated keratinocytes was measured by enzyme-linked immunosorbent assay. Results  Our results showed that serum is a very potent inducer of hBD2 and 2·5% human serum was much more potent in inducing hBD2 than 20 ng mL−1 of tumour necrosis factor-α. Interestingly, serum from patients with AD showed an impaired ability to induce hBD2 in normal keratinocytes. IL-33 significantly downregulated serum-induced hBD2. The downregulatory capacity of IL-33 was found to be 1·5- to 2-fold weaker compared with IL-4. Conclusions  Our data suggest that IL-33 can significantly contribute to the decreased expression of hBD2 in acute eczematous reaction clinically characterized by spongiosis and oozing – thus indicative for contact of the epidermis with serum components.

IL-36 gamma is a proinflamatory cytokine which belongs to the IL-1 family of cytokines. It is expressed in the skin and by epithelial cells (ECs) lining lung and gut tissue. We used human 3-D organotypic cells, that recapitulate either in vivo human vaginal or cervical tissue, to explore the possible role of IL-36 gamma in host defense against pathogens in the human female reproductive tract (FRT). EC were exposed to compounds derived from virus or bacterial sources and induction and regulation of IL-36 gamma and its receptor was determined. Polyinosinic-polycytidylic acid (poly I:C), flagellin, and synthetic lipoprotein (FSL-1) significantly induced expression of IL-36 gamma in a dose-dependent manner, and appeared to be TLR-dependent. Recombinant IL-36 gamma treatment resulted in self amplification of IL-36 gamma and its receptor (IL-36R) via increased gene expression, and promoted other inflammatory signaling pathways. This is the first report to demonstrate that the IL-36 receptor and IL-36 gamma are present in the human FRT EC and that they are differentially induced by microbial products at this site. We conclude that IL-36 gamma is a driver for epithelial and immune activation following microbial insult and, as such, may play a critical role in host defense in the FRT.

L'interleukine-33 (IL-33) est une alarmine appartenant à la famille de l'IL-1. Elle est rapidement libérée lors de stress cellulaires et participe ainsi à la réponse immunitaire en cas de danger. L'IL-33 est une cytokine pléïotrope (réponses immunitaires de type 2 dans l'allergie et les infections parasitaires et de type 1 dans les infections virales, participation à la réponse inflammatoire et à la réparation tissulaire) et son rôle dans les cancers est controversé. Nous avons émis l'hypothèse que des signaux de stress présents dans une tumeur pourraient conduire à la sécrétion de l'IL-33, qui pourrait alors jouer un rôle important dans l'activation de la réponse immunitaire dans les cancers. Dans un premier temps, nous avons montré que l'IL-33 est exprimée dans le stroma des cancers du sein, en particulier de type luminal. Plus précisément, elle est retrouvée dans le noyau des cellules endothéliales et le cytoplasme des fibroblastes et des macrophages. Les mécanismes conduisant à la sécrétion de l'IL-33 au sein des tumeurs sont en cours d'évaluation. Dans un second temps, nous avons montré qu'en combinaison avec l'IL-12, l'IL-33 potentialise les fonctions sécrétoires (notamment l'IFN-?) et cytotoxiques des cellules NK, douées de propriétés anti-tumorales. En effet, l'IL-12 induit l'expression de ST2, le récepteur de l'IL-33, sélectivement à la surface des cellules NK CD56dim, les sensibilisant ainsi à l'IL-33. En comparant l'IL-33 aux membres clés de la famille de l'IL-1, nous avons montré que contrairement à l'IL-33, i) l'IL-1a/ß activent uniquement les cellules NK CD56bright exprimant constitutivement IL-1RI et ii) l'IL-18 stimule fortement les fonctions des deux sous-populations de cellules NK qui expriment l'IL18R à l'état basal. En conclusion, nos résultats pourraient suggérer un rôle anti-tumoral potentiel de l'IL-33 via l'activation des cellules NK et ouvrent sur des stratégies thérapeutiques basées sur l'activation des cellules NK dans les cancers / IL-33 is an alarmin which belongs to the IL-1 family. Upon cellular stress, IL-33 is rapidly released and contributes to the activation of the immune system in case of danger. IL-33 has pleiotropic effects (type 2 immune responses in allergic disease or parasitic infection, type 1 immune responses in viral infection, participation to the inflammatory response and to tissue remodeling and repair) and its role in cancer is controversial. We hypothesize that upon stress related to tumor development, IL-33 could be released and activate immune responses in tumors. First, we showed that IL-33 is expressed in the stroma of breast tumors, in particular in luminal subtype. More precisely, IL-33 is expressed in the nucleus of endothelial cells and in the cytoplasm of fibroblasts and macrophages. The mechanisms responsible for IL-33 release in tumor are under investigation. Then, we demonstrated that IL-33 combined to IL-12 potentiates the secretory (particularly IFN-?) and cytotoxic functions of NK cells, which possess anti-tumoral properties. IL-12 induces ST2 (IL-33 receptor) expression selectively on CD56dim NK cells, making them sensitive to IL-33 stimulation. By comparing IL-33 to key members of the IL-1 family, we showed that in contrast to IL -33, i) IL-1a/ß activate only CD56bright NK cells, which express constitutively IL-1R and ii) IL-18 strongly activates both subsets of NK cells which express constitutively high levels of IL-18R. In conclusion, our results could support a potential anti-tumoral role of IL-33 via NK cell activation and offer new therapeutic opportunities based on NK cell activation in cancer