Researchers at the University of California, San Diego School of Medicine have discovered that a multi-tasking protein called FoxO1 has another important but previously unknown function - it directly interacts with macrophages, promoting an inflammatory response that can lead to insulin resistance and diabetes.
Contrarily, it also generates a negative feedback loop that can limit damage from excessive inflammation.
The findings by Jerrold M. Olefsky, MD, Associate Dean for Scientific Affairs and professor of Medicine, and colleagues are published in the November 2 issue of The EMBO Journal.
FoxO1 belongs to a group of well-known transcriptions factors crucial to determining the fate of cells. Earlier research has shown that FoxO1 helps govern the expression of genes involved in diabetes, cancer and aging. One unusual aspect of FoxO1 is that exposure to insulin causes cells to exclude the protein from their nuclei, inactivating it.
Olefsky and colleagues conducted a massive sequencing survey to find all of the places in the human genome where FoxO1 binds to and influences genes. They detected about 10,000 sites, but one group immediately attracted their attention: the inflammatory pathway in the macrophage – a type of white blood cell that ingests foreign invaders and is a major player in the immune response system.
The scientists discovered that FoxO1 independently binds to the promoter region of the gene for Toll-like receptor4 (TLR4), a protein on macrophages' surface that acts to bind to and recognize microbial-derived molecules. ''TLRs are the gateway to inflammatory signaling in the macrophage. They start the inflammation response,'' said Olefsky. ''Discovering that FoxO1 regulates them is a pretty critical finding.''