Interleukin (IL)-33: New Therapeutic Target for Atopic Diseases

Abstract

Abstract. Interleukin (IL)-33, a member of the IL-1 family of cytokines, is produced when epithelial and endothelial cells are exposed to stimuli. Hematopoietic cells such as macrophages also produce IL-33. IL-33 is considered to function as an 'alarmin', activating various immune cells through its receptor ST2, which leads to the production of various molecules. The IL-33-induced production of pro-inflammatory cytokines is a critical event that aggravates atopic diseases such as asthma, atopic dermatitis, and pollenosis and suggests that IL-33-blocking agents could represent new therapeutic drugs. The anti-IL-33 antibody was effective in allergic models, whereas the anti-ST2 antibody has yielded controversial results because soluble ST2 functions as a decoy receptor for IL-33. IL-33-mediated pulmonary inflammation may be glucocorticoidresistant especially when other cytokines act synergistically. Anti-tumor necrosis factor (TNF)-a therapy may also be effective against IL-33-mediated diseases. ERK1/2 inhibitors have also been shown to suppress the production of IL-33. On the other hand, activation of b 2 -receptors enhanced the expression of IL-33 mRNA in dendritic cells by activating protein kinase A (PKA), suggesting that PKA inhibitors may be candidates for IL-33-blocking agents. The effects of IL-33-blocking agents on atopic diseases need to be pharmacologically assessed in experimental and clinical studies.

IL-33 and Its Receptor ST2 after Inhaled Allergen Challenge in Allergic Asthmatics

“…IL-33 –/– mice have shown attenuated eosinophil influx into the BALF and Th2 inflammation [33]. Similarly, anti-IL-33 mAb inhibited eosinophil recruitment and Th2 cytokine production [16, 34]. …”

Decreased expression of IL-33 in immune thrombocytopenia

“…In addition to the membrane form of ST2, there is also soluble ST2 in plasma which has no trans-membrane sequence and can be a decoy receptor for IL-33 [41]. IL-33 binding to sST2 can inhibit the IL-33/ST2 pathway [41].…”

“…IL-33 binding to sST2 can inhibit the IL-33/ST2 pathway [41]. In systemic lupus erythematosus (SLE), sST2 was proven to be associated with an active disease state in patients.…”

Targeting IL-33 in Autoimmunity and Inflammation

“…Targeting IL-33 has been considered as a therapeutic target for atopic (Nabe, 2014), rheumatic (Duan et al, 2013), and autoimmune diseases . Administration of sST2 to murine splenocytes inhibited production of Th2 cytokines (e.g., IL-4 and IL-5) but not of Th1 (e.g., IFN-g) (Lohning et al, 1998).…”