Mechanisms involved in enhancement of matrix metalloproteinase‐9 expression in macrophages by interleukin‐33

Endothelial transmigration of macrophages is accomplished by matrix metalloproteinase (MMP)‐induced degradation of the basement membrane and extracellular matrix components. Macrophages upregulate MMP‐9 expression and secretion upon immunological challenges and require its activity for migration during inflammatory responses. Interleukin (IL)‐33 is a recently discovered pro‐inflammatory cytokine that belongs to the IL‐1 family. The aim of this study was to elucidate the mechanisms underlying IL‐33‐induced MMP‐9 expression in the mouse monocyte/macrophage line RAW264.7. IL‐33 increased MMP‐9 mRNA and protein expression in RAW264.7 cells. Blockage of IL‐33‐IL‐33 receptor (ST2L) binding suppressed IL‐33‐mediated induction of MMP‐9. IL‐33 induced phosphorylation and nuclear translocation of extracellular signal‐regulated kinase 1/2 (ERK1/2) and nuclear factor‐kappa B (NF‐κB). Chromatin immunoprecipitation indicated that IL‐33 increased c‐fos recruitment to the MMP‐9 promoter. Reporter assay findings also revealed that IL‐33 stimulated the transcriptional activity of activator protein 1 (AP‐1). Pre‐treatment of the cells with a specific inhibitor of ERK1/2 and NF‐κB attenuated the IL‐33‐induced activation of AP‐1 subunits, transcriptional activity of AP‐1, and expression of MMP‐9. We also demonstrated that ERK‐dependent activation of cAMP response element binding protein (CREB) is a key step for AP‐1 activation by IL‐33. These results indicate an essential role of ERK/CREB and NF‐κB cascades in the induction of MMP‐9 in monocytes/macrophages through AP‐1 activation. IL‐33‐ST2L interaction increased MMP‐9 expression in RAW264.7 cells. ERK/CREB and NF‐κB cascades have an essential role in the induction of MMP‐9 in monocytes/macrophages through AP‐1 activation.