- Guide to PHARMACOLOGY
Compound class: Endogenous peptide in human, mouse or rat
Comment: IL-33 is a pleiotropic IL-1 family cytokine that can both promote type 2 inflammation and also drive immunoregulation through expansion of Foxp3+Treg cells. The outcomes of IL-33 activity appear to depend on the cells that produce it, either myeloid dendritic cells (DC) or epithelial cells . DC-derived IL-33 supports Treg cells. The main cellular targets of IL-33 are innate lymphoid cells type 2 (ILC2), involved in the initiation of the type 2 immune response (secretion of IL-5 and IL-13) during parasitic infection and allergic diseases such as asthma. Full length IL-33 is cleaved by mast cell chymase (chymase 1; CMA1) to produce its significantly more active form .
The ST2/IL-33 axis is recognised as playing an important role in the development/exacerbation of IgE-dependent inflammations such as asthma and atopic dermatitis [1,4], and received much interest from the pharmaceutical industry. Blockade of IL-33 activity (and/or its receptor ST2) represent potential novel mechanisms for pharmaceutical intervention to suppress allergy and mast cell-eosinophil interplay. Indeed, astegolimab (RG6149/AMG 282) is an example of a fully human anti-IL-33 monoclonal antibody, that was developed as a potential therapy for mild atopic asthma and chronic rhinosinusitis. Unfortunalely, in common with other anti-IL-33 leads, RG6149 failed to deliver clinical efficacy in these indications.