IL-36 cytokines in inflammatory and malignant diseases: not the new kid on the block anymore

Byrne, James; Baker, Kevin J.; Houston, Aileen; Brint, Elizabeth

doi:10.1007/s00018-021-03909-4

Cited by 27 publications

(25 citation statements)

References 107 publications

(140 reference statements)

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“…Whilst each of the IL-1 family members has been shown to have pro and anti-tumorigenic effects to date, IL-36-related studies to date have shown primarily anti-tumorigenic roles [ 31 , 36 ]. Given the complex divergent nature of IL-1 family members across many pathologies including cancers, it is of little surprise that IL-36R signalling may indeed have both pro- and anti- tumorigenic effects, especially in a complex disease such as CRC.…”

Section: Discussionmentioning

confidence: 99%

IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist

et al. 2022

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The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, shown to play a role in the pathogenesis of intestinal diseases such as Inflammatory Bowel Disease (IBD). Given the link between IBD and colitis –associated cancer, as well as the involvement of other IL-1 family members in intestinal tumorigenesis, the aim of this work was to investigate whether IL-36 cytokines play a role in the pathogenesis of colon cancer. Whilst research to date has focused on the role of IL-36 family members in augmenting the immune response to induce tumour rejection, very little remains known about IL-36R signalling in tumour cells in this context. In this study we demonstrate that expression of IL-36 family member mRNA and protein are significantly increased in colorectal cancer tissue compared to adjacent non-tumour. In vitro assays showed stimulation of colon cancer cell lines with IL-36R agonists resulted in the activation of the pro-tumorigenic phenotypes of increased cellular migration, invasion and proliferation in both 2D and 3D models. In addition, the IL-36 cytokines induced strong expression of pro-inflammatory chemokines in both human and murine cell lines. Intraperitoneal injection of IL-36Ra significantly reduced tumour burden using the subcutaneous CT26 tumour model in syngeneic Balb/mice, and this was associated with a decrease in Ki-67 expression by tumour cells in the IL-36Ra- treated group relative to untreated, suggesting the inhibition of the pro-proliferative signalling of IL-36 agonists resulted in the decreased tumour size. Moreover, colon cancer cells lacking the IL-36R also showed reduced tumour growth and reduced Ki-67 expression in vivo. Taken together, this data suggests that targeting IL-36R signalling may be a useful targeted therapy for colorectal cancer patients with IL-36R+ tumour cells.

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Section: Discussionmentioning

confidence: 99%

IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist

et al. 2022

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“…IL-36γ is crucial in the regulation of immune responses and chronic inflammatory and fibrotic disorders ( 11 , 14 , 16 ). However, little is known about its regulation and functions in the AT inflammation in obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas IL-36a, -b, and -g trigger immune cell infiltration and inflammatory pathways through the activation of IL-36R, the IL-36Ra functions as an anti-inflammatory factor by inhibiting IL-36R signaling (11)(12)(13). IL-36 isoforms are expressed by a broad variety of tissues and multiple cell types with their ultimate effects depending on a fine balance of their concentrations, the cellular target or the phase and context of the disease (11,14,15). Therefore, IL-36 has been implicated in multiple diseases with an inflammatory component including psoriasis, inflammatory bowel diseases, arthritis and joint diseases, renal and pulmonary injuries and even cancer (14,16), but little information about the impact of IL-36 on obesity-associated inflammation exists (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…IL-36 isoforms are expressed by a broad variety of tissues and multiple cell types with their ultimate effects depending on a fine balance of their concentrations, the cellular target or the phase and context of the disease (11,14,15). Therefore, IL-36 has been implicated in multiple diseases with an inflammatory component including psoriasis, inflammatory bowel diseases, arthritis and joint diseases, renal and pulmonary injuries and even cancer (14,16), but little information about the impact of IL-36 on obesity-associated inflammation exists (17)(18)(19). Higher circulating levels of IL-36g and IL-36a together with decreased levels of IL-36Ra have been found in patients with obesity (19) and T2D (18).…”

Section: Introductionmentioning

confidence: 99%

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Increased Levels of Interleukin-36 in Obesity and Type 2 Diabetes Fuel Adipose Tissue Inflammation by Inducing Its Own Expression and Release by Adipocytes and Macrophages

et al. 2022

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Interleukin (IL)-36 is a recently described cytokine with well-known functions in the regulation of multiple inflammatory diseases. Since no data exists on how this cytokine regulates adipose tissue (AT) homeostasis, we aimed to explore the function of a specific isoform, IL-36γ, an agonist, in human obesity and obesity-associated type 2 diabetes as well as in AT inflammation and fibrosis. Plasma IL-36γ was measured in 91 participants in a case-control study and the effect of weight loss was evaluated in 31 patients with severe obesity undergoing bariatric surgery. Gene expression levels of IL36G and its receptor were analyzed in relevant human metabolic tissues. The effect of inflammatory factors and IL-36γ was determined in vitro in human adipocytes and macrophages. We found, for the first time, that the increased (P<0.05) circulating levels of IL-36γ in patients with obesity decreased (P<0.001) after weight and fat loss achieved by Roux-en-Y gastric bypass and that gene expression levels of IL36G were upregulated in the visceral AT (P<0.05) and in the peripheral blood mononuclear cells (P<0.01) from patients with obesity. We also demonstrated increased (P<0.05) expression levels of Il36g in the epididymal AT from diet-induced obese mice. IL36G was significantly enhanced (P<0.001) by LPS in human adipocytes and monocyte-derived macrophages, while no changes were found after the incubation with anti-inflammatory cytokines. The addition of IL-36γ for 24 h strongly induced (P<0.01) its own expression as well as key inflammatory and chemoattractant factors with no changes in genes associated with fibrosis. Furthermore, adipocyte-conditioned media obtained from patients with obesity increased (P<0.01) the release of IL-36γ and the expression (P<0.05) of cathepsin G (CTSG) in monocyte-derived macrophages. These findings provide, for the first time, evidence about the properties of IL-36γ in the regulation of AT-chronic inflammation, emerging as a link between AT biology and the obesity-associated comorbidities.

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“…Here we have demonstrated that IL-36g is secreted through an unconventional secretory pathway type I, specifically through the P2X7R and GSDMD membrane pores in a mechanism dependent on LPS/ATP stimulation. As P2X7R/GSDMD have an important role in the secretion of IL-36g; thus, we believe that blocking these pores can be a novel therapeutic approach to limit IL-36 cytokines bioavailability in several autoimmune diseases, cancer, obesity, and chronic inflammatory pain, among others, and ameliorate symptoms, as has been proposed elsewhere (33,34).…”

Section: Discussionmentioning

confidence: 77%

IL-36γ is secreted through an unconventional pathway using the Gasdermin D and P2X7R membrane pores

et al. 2022

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Mucosal innate immunity functions as the first line of defense against invading pathogens. Members of the IL-1 family are key cytokines upregulated in the inflamed mucosa. Inflammatory cytokines are regulated by limiting their function and availability through their activation and secretion mechanisms. IL-1 cytokines secretion is affected by the lack of a signal peptide on their sequence, which prevents them from accessing the conventional protein secretion pathway; thus, they use unconventional protein secretion pathways. Here we show in mouse macrophages that LPS/ATP stimulation induces cytokine relocalization to the plasma membrane, and conventional secretion blockade using monensin or Brefeldin A triggers no IL-36γ accumulation within the cell. In silico modeling indicates IL-36γ can pass through both the P2X7R and Gasdermin D pores, and both IL-36γ, P2X7R and Gasdermin D mRNA are upregulated in inflammation; further, experimental blockade of these receptors’ limits IL-36γ release. Our results demonstrate that IL-36γ is secreted mainly by an unconventional pathway through membrane pores formed by P2X7R and Gasdermin D.

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IL-36 cytokines in inflammatory and malignant diseases: not the new kid on the block anymore

Cited by 27 publications

References 107 publications

IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist

IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist

Increased Levels of Interleukin-36 in Obesity and Type 2 Diabetes Fuel Adipose Tissue Inflammation by Inducing Its Own Expression and Release by Adipocytes and Macrophages

IL-36γ is secreted through an unconventional pathway using the Gasdermin D and P2X7R membrane pores

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