Multifaceted roles of IL-38 in inflammation and cancer

Díaz-Barreiro, Alejandro; Huard, Arnaud; Palmer, Gaby

doi:10.1016/j.cyto.2022.155808

Cited by 19 publications

(13 citation statements)

References 99 publications

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“…IL-38 is the latest added member of the IL-1 family of cytokines, but in the last few years it has already been shown to be dysregulated in a wide range of diseases such as cancer, infectious diseases, and autoimmunity ( 6 , 7 ). Patients with atopic dermatitis ( 20 ), influenza ( 21 ), SLE ( 22 ), rheumatoid arthritis ( 25 , 39 ), myocardial infarction ( 23 ), sepsis ( 24 ), acquired immune-mediated neuropathies ( 31 ), osteoarthritis ( 32 ), acute respiratory distress syndrome ( 35 ), inflammatory bowel disease ( 33 ), type 2 diabetes ( 41 ), and vitiligo ( 43 ) present with higher blood concentrations of IL-38.…”

Section: Discussionmentioning

confidence: 99%

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Circulating interleukin-38 concentrations in healthy adults

Teufel

Graaf²,

Netea³

et al. 2022

Front. Immunol.

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Interleukin (IL)-38 is the latest discovered member of the interleukin-1 family, which has anti-inflammatory properties similar to IL-36Ra. Several studies compared circulating IL-38 concentrations in healthy and diseased populations to characterize its role in both auto-immune and inflammatory pathologies, with both higher and lower concentrations being associated with certain diseases. However, in order to use IL-38 as a biomarker, a reference range in healthy adults is needed. To establish a reference IL-38 circulating concentration, accessible data from 25 eligible studies with IL-38 concentrations in healthy adults was collected. To validate the values found in literature, we measured IL-38 concentrations by enzyme-linked immunosorbent assay (ELISA) in several cohorts from our own institute. Additionally, the effect of blood collection techniques, freeze thawing cycles, and hemolysis on IL-38 measurements was assessed. To evaluate the importance of the genetic background of individuals as confounding factor of IL-38 synthesis, we used publicly available eQTL databases with matched data on allele frequencies in individuals of different ethnicities. Mean IL-38 concentrations in the various studies were weighted by their corresponding sample size, resulting in a weighted mean, and weighted upper and lower limits were calculated by mean ± 2 SD. Differences of over 10.000-fold were found in the weighted means between studies, which could not be attributed to the blood collection method or assessment of IL-38 in plasma or serum. Although IL-38 concentrations were markedly higher in Chinese then in European population studies, we could not show an association with the genetic background. From our analysis, a reference range for circulating IL-38 in healthy adults could thus not yet be established.

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Section: Discussionmentioning

confidence: 99%

“…With regard to its role in health and disease, aberrant IL-38 concentrations have been observed in different types of diseases such as auto-immune diseases, infections, or acute cardiovascular events ( 6 , 7 ). Evidence of IL-38’s acute role in response to local or systemic infections, however, is scarce.…”

Section: Introductionmentioning

confidence: 99%

Circulating interleukin-38 concentrations in healthy adults

Teufel

Graaf²,

Netea³

et al. 2022

Front. Immunol.

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“…However, our data so far do not exclude the possibility that endogenous IL-38 acts through B cell surface receptors. The primary mode in which IL-38 signaling through its putative cell surface receptors affects cell biology suggested so far in the literature is affecting cytokine production [ 7 , 39 , 40 ]. Transient knockdown of IL-38 increased the levels of IL-2, IL-6, and IL-10 at different time points, all of which are known to promote B cell differentiation and/or survival [ 41 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Cell Intrinsic IL-38 Affects B Cell Differentiation and Antibody Production

Huard

Wilmes

Kiprina

et al. 2023

IJMS

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IL-38 is an IL-1 family receptor antagonist with an emerging role in chronic inflammatory diseases. IL-38 expression has been mainly observed not only in epithelia, but also in cells of the immune system, including macrophages and B cells. Given the association of both IL-38 and B cells with chronic inflammation, we explored if IL-38 affects B cell biology. IL-38-deficient mice showed higher amounts of plasma cells (PC) in lymphoid organs but, conversely, lower levels of plasmatic antibody titers. Exploring underlying mechanisms in human B cells revealed that exogenously added IL-38 did not significantly affect early B cell activation or differentiation into plasma cells, even though IL-38 suppressed upregulation of CD38. Instead, IL-38 mRNA expression was transiently upregulated during the differentiation of human B cells to plasma cells in vitro, and knocking down IL-38 during early B cell differentiation increased plasma cell generation, while reducing antibody production, thus reproducing the murine phenotype. Although this endogenous role of IL-38 in B cell differentiation and antibody production did not align with an immunosuppressive function, autoantibody production induced in mice by repeated IL-18 injections was enhanced in an IL-38-deficient background. Taken together, our data suggest that cell-intrinsic IL-38 promotes antibody production at baseline but suppresses the production of autoantibodies in an inflammatory context, which may partially explain its protective role during chronic inflammation.

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“…Finally, the IL-38 axis presents opposite effects depending on the type of cancer. Indeed, it was found to decrease and be associated with anti-tumor function in CRC, while in PDL-1-negative lung carcinoma, IL-38 was associated with a pro-tumorigenic effect [ 141 , 144 ].…”

Section: Role Of Il-1rap In Tumorsmentioning

confidence: 99%

IL-1RAP, a Key Therapeutic Target in Cancer

Frenay

Bellaye

Oudot

et al. 2022

IJMS

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Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.

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Multifaceted roles of IL-38 in inflammation and cancer

Cited by 19 publications

References 99 publications

Circulating interleukin-38 concentrations in healthy adults

Circulating interleukin-38 concentrations in healthy adults

Cell Intrinsic IL-38 Affects B Cell Differentiation and Antibody Production

IL-1RAP, a Key Therapeutic Target in Cancer

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