Serum Amyloid A Induces Interleukin-33 Expression Through an IRF7-dependent Pathway

Interleukin-33 (IL-33), an IL-1 family cytokine and nuclear alarmin, is constitutively expressed in epithelial barrier tissues and human blood vessels. However, little is known about the induced expression of IL-33 in monocytes and macrophages, which are major cytokine-producing cells of the innate immune system. Here, we report the induction of IL33 expression in both human monocytes and mouse macrophages from C57BL/6 mice by the acute-phase protein serum amyloid A (SAA). SAA-induced transcriptional activation of the Il33 gene, resulting in nuclear accumulation of the IL-33 protein. TLR2, one of the SAA receptors, was primarily responsible for the induction of IL-33. Progressive deletion of the human IL-33 promoter led to the identification of two potential binding sites for interferon regulatory factor 7 (IRF7), one of which (-277/-257) was found to be important for SAA-stimulated IL-33 promoter activity. IRF7 was recruited to the IL-33 promoter upon SAA stimulation, and silencing IRF7 expression in THP-1 cells abrogated SAA-induced Il33 expression. SAA also promoted an interaction between TNF receptor-associated factor 6 and IRF7. Taken together, these results identify IRF7 as a critical transcription factor for SAA-induced Il33 expression in monocytes and macrophages.