Interleukin-33 and Obesity-Related Inflammation and Cancer

Abstract

Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family. It is primarily associated with type 2 immune responses. It interacts with a receptor complex on immune cells in reaction to tissue damage or cellular injury. IL-33 is crucial in immune responses and is involved in various autoimmune and inflammatory diseases. Obesity is marked by chronic inflammation and is a known risk factor for several types of cancer. Recent studies have shown that IL-33 and its receptor complex are expressed in adipose (fat) tissue, suggesting they may play a role in obesity. While inflammation connects obesity and cancer, it is not yet clear whether IL-33 contributes to cancer associated with obesity. Depending on the cellular context, inflammatory environment, expression levels, and bioactivity, IL-33 can exhibit both protumorigenic and antitumorigenic effects. This review will explore the various functions of IL-33 in the inflammation linked to obesity and its relationship with cancer.

Keywords: IL-33; ST2; cancer; immune response; inflammation; obesity.

Figure 1.

The human IL-33 gene and the IL-33 and ST2 proteins. (A) The human IL33 gene is located on the short arm of chromosome 9 at 9p24.1. A large intron (25.8 kb; intron 1) separates the first non-coding exon (exon 1, also designated exon 1a) from the first coding exon (exon 2). An alternative exon 1b is located 4.6 kb upstream of exon 2. (B) Structure of the human IL-33 protein. It comprises two evolutionary conserved domains (the nuclear and IL-1-like cytokine domains) separated by a highly divergent linker region in the center (the central domain). Chromatin-binding motif and cleavage sites for caspases and inflammatory proteases are indicated. (C) The IL1RL1 gene encodes the ST2 protein. In humans, ST2 was identified in 3 splicing variants (not shown), but only the proteins ST2L and sST2 were identified in human cells [39].

Figure 2.

The IL-33/ST2 signaling pathway. When stromal cells experience damage or mechanical injury, they undergo necrosis and release IL-33. This cytokine activates the heterodimeric ST2/IL-1RAcP receptor complex on various immune cells. IL-33 can also bind to a decoy receptor composed of a soluble form of ST2 (sST2) or SIGIRR, which leads to inactivation. Upon activation of the ST2L, TIR initiates the pathway by first recruiting MyD88, which induces recruitment of IRAK1 and IRAK4, similar to the binding process seen with other interleukin-1 family members, such as Il-1α and IL-1β. This recruitment activates the transcription factor nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathways. The activation is mediated by the MAPKs, including extracellular signal-regulated kinase (ERK), p38, and JUN N-terminal kinase (JNK), ultimately producing Th2 cytokines and chemokines. The activity of MAPK pathways and canonical NF-κB is regulated at multiple levels. ST2L, suppression of tumorigenicity 2 ligand; IL-1RAcP, IL-1 receptor accessory protein; MyD88, myeloid differentiation primary response protein 88; IRAK1, interleukin receptor-associated kinase 1; IRAK4, interleukin receptor-associated kinase 4;TRAF6, tumor necrosis factor receptor-associated factor 6; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinases 1/2; JNK, c-Jun N-terminal kinase; p38, the subgroup of MAP kinases; AP-1, transcription factor; NF-κB, nuclear factor κB; TAK1, transforming growth factor (TGF)-β-activated protein kinase 1; NEMO, NF-κB essential modulator; IKKβ, inhibitor of κB (IκB) kinase β. This figure was created with BioRender.

Figure 3.

The production of IL-33 and the distribution of ST2. (A) Various immune cells release IL-33 in response to cell stress and injury. Under pathological conditions, IL-33 is released by endothelial and epithelial cells of barrier tissues such as the lung, intestine, skin, and fibroblasts, as well as glial cells, astrocytes, smooth muscle cells, platelets, and several types of immune cells, including macrophages (Mφ), dendritic cells (DCs), immature dendritic cells (imDCs), and mast cells. (B)Active IL-33 signals through ST2, expressed in different types of immune cells, including innate lymphoid cells and adaptive immune cells, generate different cytokines or polarize into the corresponding phenotypes in different pathological conditions. This figure was created with BioRender.

Figure 4.

IL-33 and ST2 immune cells in adipose tissue. During the development of obesity, adipocyte hypertrophy is accompanied by significant changes in immune cell populations. Most immune cells increase in quantity in adipose tissue due to obesity, with a few exceptions, including regulatory T cells (Tregs) and eosinophils. Tregs and eosinophils reduce the inflammatory responses of other immune cells in adipose tissue, particularly adipose tissue macrophages. As obesity progresses, the population of IL-33/ST2 target immune cells in adipose tissue also varies, leading to obesity-related inflammation. Lean adipose tissue primarily contains non-inflammatory cells, such as activated M2 macrophages (M2φ), eosinophils, ILC2 cells, Tregs, and Th2 cells. In contrast, obesity shifts the immune profile of adipose tissue toward a pro-inflammatory state, characterized by an influx of macrophages (M1φ), NK cells, neutrophils, CD4⁺ T cells (Th1, Th17), and CD8⁺ T cells. When IL-33 is reduced during obesity, sST2 is increased [108], which can inhibit metabolic health. In addition, the balance between Th1 and Th2 cells, and between Treg and Th17 cells, is disrupted, leading to increased adipose tissue-related inflammation (often referred to as “met-inflammation”) and contributing to the development of metabolic diseases. DC, dendritic cell; M, macrophage; ILC2, innate lymphoid cell type 2; iNKT, invariant natural killer T; NK, natural killer cells; NKT, natural killer T cells; MDSC, myeloid-derived suppressor cells. This figure was created with BioRender.

Figure 5.

Role of IL-33 in the tumor microenvironment: IL-33 influences immune regulation and can have both protumor and antitumor effects. The population of immune cells targeted by IL-33/ST2 in the TME changes depending on the context. This results in opposing effects in different tumors. Along with tumor development, IL-33 is likely downregulated in epithelial cells but upregulated in the tumor microenvironment. The increased IL-33 expression in stroma either maintains or activates suppressor immune cells such as macrophages, Tregs, and CD4⁺ Th2 or Th17 cells, thus contributing to tumor growth and metastasis. However, IL-33 may also have an antitumor effect by activating innate natural killer (NK) cells and adaptive (CD4⁺ Th1 or CD8⁺ T cells) immune responses. IL-33/ST2 signaling can lead to a dual role on other cell types such as eosinophils, basophils, group 2 innate lymphoid cells (ILC2s), and myeloid-derived suppressor cells (MDSCs) either directly or through interaction with other cell types, depending on cancer type [123]. Cell names in red indicate that their primary function is a protumor effect; cell names in blue indicate that their primary function is an antitumor effect; cell names in green indicate dual roles. The cells are named in black, and their primary functions are on the corresponding side. This figure was created with BioRender.