IL-33/ST2 axis in inflammation and immunopathology

Abstract

Interleukin-33 (IL-33), a member of the IL-1 family of cytokines, binds to its plasma membrane receptor, heterodimeric complex consisted of membrane-bound ST2L and IL-1R accessory protein, inducing NFkB and MAPK activation. IL-33 exists as a nuclear precursor and may act as an alarmin, when it is released after cell damage or as negative regulator of NFκB gene transcription, when acts in an intracrine manner. ST2L is expressed on several immune cells: Th2 lymphocytes, NK, NKT and mast cells and on cells of myeloid lineage: monocytes, dendritic cells and granulocytes. IL-33/ST2 axis can promote both Th1 and Th2 immune responses depending on the type of activated cell and microenvironment and cytokine network in damaged tissue. We previously described and discuss here the important role of IL-33/ST2 axis in experimental models of type 1 diabetes, experimental autoimmune encephalomyelitis, fulminant hepatitis and breast cancer. We found that ST2 deletion enhance the development of T cell-mediated autoimmune disorders, EAE and diabetes mellitus type I. Disease development was accompanied by dominantly Th1/Th17 immune response but also higher IL-33 production, which suggest that IL-33 in receptor independent manner could promote the development of inflammatory autoreactive T cells. IL-33/ST2 axis has protective role in Con A hepatitis. ST2-deficient mice had more severe hepatitis with higher influx of inflammatory cells in liver and dominant Th1/Th17 systemic response. Pretreatment of mice with IL-33 prevented Con A-induced liver damage through prevention of apoptosis of hepatocytes and Th2 amplification. Deletion of IL-33/ST2 axis enhances cytotoxicity of NK cells, production of IFN-γ in these cells and systemic production of IFN-γ, IL-17 and TNF-α, which leads to attenuated tumor growth. IL-33 treatment of tumor-bearing mice suppresses activity of NK cells, dendritic cell maturation and enhances alternative activation of macrophages. In conclusion, we observed that IL-33 has attenuated anti-inflammatory effects in T cell-mediated responses and that both IL-33 and ST2 could be further explored as potential therapeutic targets in treatment of immune-mediated diseases.

Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer

“…It has been revealed that IL-33 can stimulate angiogenesis and cell growth via its receptor ST2 expressed in the effecting cells (20,46). In this study we have observed that ST2 was expressed in both the adenomatous/cancerous epithelium and microvessels, whether IL- LGD: Lower grade dysplasia.…”

“…The role of IL-33/ST2 in tumors has been investigated; however, the involvement of IL-33 in different human tumors is controversial. It has been reported that the IL-33/ST2 pathway may play an active role in inhibiting antitumor immunity, promoting metastasis in breast cancer (19)(20)(21) and acting as a crucial mediator in inflammation-associated pancreatic carcinogenesis (22).…”

Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

“…It has been proposed that the IL-33/IL-13 axis promotes liver fibrosis (25). A number of different cell types have been identified as candidates for IL-13 production upon IL-33 stimulation, including T cells and macrophages (24,48,49 Figure 5C). …”

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

“…IL-33 is an IL-1 family cytokine that regulates a wide array of pathological states associated with cardiovascular disease, rheumatoid arthritis, anaphylaxis, ulcerative colitis, and pathogen infestation (9,10). Like other IL-1 family members, IL-33 can be cleaved by caspase-1, although it appears that this cleavage leads to functional inactivation (11), leading to speculation that IL-33 primarily functions as a chromatin-associated nuclear factor (12).…”