The ST2/Interleukin-33 Axis in Hematologic Malignancies: The IL-33 Paradox

Abstract

Interleukin (IL)-33 is a chromatin-related nuclear interleukin that is a component of IL-1 family. IL-33 production augments the course of inflammation after cell damage or death. It is discharged into the extracellular space. IL-33 is regarded as an “alarmin” able to stimulate several effectors of the immune system, regulating numerous immune responses comprising cancer immune reactions. IL-33 has been demonstrated to influence tumorigenesis. However, as far as this cytokine is concerned, we are faced with what has sometimes been defined as the IL-33 paradox. Several studies have demonstrated a relevant role of IL-33 to numerous malignancies, where it may have pro- and—less frequently—antitumorigenic actions. In the field of hematological malignancies, the role of IL-33 seems even more complex. Although we can affirm the existence of a negative role of IL-33 in Chronic myelogenos leukemia (CML) and in lymphoproliferative diseases and a positive role in pathologies such as Acute myeloid leukemia (AML), the action of IL-33 seems to be multiple and sometimes contradictory within the same pathology. In the future, we will have to learn to govern the negative aspects of activating the IL-33/ST2 axis and exploit the positive ones.

IL-33/Vitamin D Crosstalk in Psoriasis-Associated Osteoporosis

“…IL-33 reinforces the TNF-alpha induced secretion of IL-6, VEGF, and MCP-1. However, data on IL-33 serum levels in Pso are controversial ( 113 ). A large number of studies suggest that a localized, rather than a generalized, IL-33 linked inflammatory pattern is evident in Pso ( 114 ).…”

“…The MAPK-activated protein kinases MK2 and MK3, function as sensors of cell injury and exert pivotal roles in IL-33-induced cytokine production by mast cells in inflammatory responses ( 87 , 98 , 107 ). Due to its pleiotropic nature, IL-33 exerts contrasting roles in different diseases ( 87 , 88 ), i.e., IL-33 can either drive the underlying inflammation or promote its resolution ( 99 , 113 ) according to the individual inflammatory context. Disease severity and changes in relation to hormonal influences contribute to the bone remodeling effects of IL-33.…”

“…Furthermore, most studies have shown compartmentalization of IL-33 in Pso with increased concentrations in skin lesions but not in the serum ( 114 ), potentially explaining the lack of protective effects on bone. The final effect of the IL-33/ST2 axis in both Pso and OP therefore depends on the reciprocal relationship between its various components which influence each other through complex regulatory mechanisms and positive and negative feedback circuits ( 113 ). For example, the effect of an increase in IL-33 could be counterbalanced by a consensual increase in its decoy receptor sST2 or, on the contrary, it could be enhanced by increased expression of its receptor on different cell types ( 66 ).…”

The IL-33/ST2 Axis in Immune Responses Against Parasitic Disease: Potential Therapeutic Applications

“…In general, IL-33 as well as ST2 have been implicated in enhanced pathology and progression of colorectal, lung, breast and gastric cancer, as well as melanoma, head and neck squamous cell carcinoma and cholangiocarcinoma (Gorbacheva and Mitkin, 2019;Hong et al, 2019). In terms of hematological malignancies, the effects of IL-33 are controversial as a negative role has been identified for Chronic myelogenous leukemia (CML), while a positive role was shown for Acute myeloid leukemia (AML) (Allegra et al, 2019). A very recent paper by Yue et al showed that IL-33 stimulates the recruitment of Tregs through the NF-kB/CCL2 pathway, thereby enhancing tumor growth and metastasis in esophageal squamous cell carcinoma (Yue et al, 2019).…”

“…However, in the context of cancer, IL-33 aids in tumor immune evasion by upregulating the activity, survival and expansion of myeloid derived suppressor cells via ST2 signaling, which was reduced in ST2 −/− mice (Xiao et al, 2016). Recent discoveries have further suggested that IL-33 can induce the proliferation, survival, and metastasis of cancer cells (Allegra et al, 2019;Gorbacheva and Mitkin, 2019). IL-33 is also known to exacerbate asthmatic and allergic inflammation in the skin, GI tract and lungs through the ST2-mediated activation of basophils, eosinophils, mast cells, dendritic cells, macrophages and ILC2s by promoting the chemo-attraction of Th2 cells and the production of Th2-associated cytokines by various cell types (Louten et al, 2011;Bartemes et al, 2012;Sjoberg et al, 2017;Chan et al, 2019).…”