IL33: A key cytokine in inflammation and its therapeutic intervention

• Gene Information: Interleukin 33 (IL33) is a protein-coding gene located on chromosome 9p24.1. It encodes an alarmin cytokine that belongs to the interleukin-1 (IL-1) family.
• Protein Expression: IL-33 is constitutively expressed in the nuclei of endothelial cells, epithelial cells (lung, gut), and skin keratinocytes. It acts as an intracellular nuclear factor under steady state but is released as a full-length active cytokine upon cell damage or mechanical stress.
• Signaling Pathway: Extracellular IL-33 exerts its effects by binding to a heterodimeric receptor complex consisting of the specific receptor ST2 (also known as IL-1RL1) and the co-receptor IL-1 receptor accessory protein (IL-1RAcP).
• Therapeutic Inhibition: By blocking the IL-33/ST2 signaling pathway, targeted therapeutics (such as anti-IL-33 or anti-ST2 monoclonal antibodies) inhibit downstream type 2 and non-type 2 inflammation, leading to reduced tissue eosinophils, lowered airway hyperresponsiveness, and decreased secretion of pro-inflammatory cytokines.

IL33

• Exons 2-8 of mouse IL33 gene that encode the whole molecule (ATG to STOP codon) were replaced by human counterparts in B-hIL33 mice.
• The promoter, 5’UTR and 3’UTR region of the mouse gene are retained. allowing human IL33 expression to be driven by the native mouse IL33 promoter, while endogenous mouse IL33 transcription and translation are abolished

• Mouse IL33 was detected exclusively in wild-type C57BL/6 mice
• Human IL33 was detected in homozygous B-hIL33 mice, but not in wild-type mice.

Strain specific IL33 expression analysis in homozygous B-hIL33 mice by ELISA. Lung tissue homogenate were collected from wild-type C57BL/6 mice and homozygous B-hIL33 mice. Mouse and human IL33 levels in lung tissue homogenates were quantified by ELISA (mouse IL33, R&D Systems M3300; human IL33, R&D Systems D3300B).