Interleukin‐8 Regulation by Histone Deacetylase Inhibitors and Bortezomib in Human Macrophages

Abstract

Interleukin‐8 (IL‐8) is a proinflammatory chemokine that plays a major role in inflammatory responses, as well as in tumor‐associated angiogenesis and tumor progression. Macrophages at the sites of tissue injury and cancer development are the major source of IL‐8. The transcriptional regulation of IL‐8 is mediated by the transcription factor NFκB. However, our previous results suggested that different mechanisms regulate the NFκB‐dependent transcription of IL‐8 and other cytokines, such as TNF, IL‐1 and IL‐6, in human macrophages. The goal of this study was to investigate the transcriptional regulation of IL‐8 in stimulated U‐937 human macrophages. Using chromatin immunoprecipitation, we show that while the NFκB promoter sites of TNF, IL‐1 and IL‐6 are occupied by p65 NFκB acetylated on K310, IL‐8 promoter is occupied by non‐acetylated p65. The histone deacetylase (HDAC) inhibitor, trichostatin A, enhances IL‐8, but not TNF transcription in stimulated macrophages, indicating that p65 K310 acetylation increases IL‐8 transcription. The proteasome inhibitor bortezomib, which down‐regulates HDACs expression, also increased IL‐8 expression in macrophages. Since HDAC inhibitors and bortezomib have emerged as promising new anti‐cancer therapies, understanding the mechanisms how they increase IL‐8 expression in macrophages may contribute to the development of more effective therapies.Funded by: NIH grants GM079581 and AI085497 to I.V.