Macrophage protein has major role in inflammation

Nov 02, 2010

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 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 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 response," said Olefsky. "Discovering that FoxO1 regulates them is a pretty critical finding."

Specifically, Olefsky said FoxO1 behaves like a priming agent. "It gets the macrophage armed and ready." That in itself is not necessarily a problem. Indeed, it's probably part of FoxO1's normal function. But in people suffering from obesity or type 2 diabetes, FoxO1 can exacerbate an already existing problem of chronic inflammation. It can make already overabundant macrophages even more responsive, essentially pouring gasoline on an inflammatory fire.

The initiation of an inflammatory response by FoxO1 also begins the process of ending it – at least in healthy systems. "FoxO1 primes to respond exuberantly to inflammation, but obviously you don't want that to go on very long," said Olefsky. "So the macrophage pumps out inflammatory cytokines that go off to do their thing, but these cytokines also come back and work on the macrophage, inducing FoxO1 to leave the nucleus and deactivate. It's a pretty robust response, though usually you need more than one of these negative feedback loops to control a process."

The discovery of FoxO1's role adds another important element to a fuller understanding of how the inflammatory process and the immune system work, Olefsky said. It helps explain how obesity and type 2 diabetes, which result in reduced insulin signaling, can lead to enhanced inflammation.

Practical applications for the new findings are less clear. FoxO1 is not a typical target for therapeutic drugs. Drug manufacturers would have to devise a novel method to interfere with FoxO1. "A small molecule might do it," said Olefsky. "That's possible, but right now that's an unknown."

Explore further: Tackling illness in premature babies with genetics and artificial noses

add to favorites email to friend print save as pdf

Related Stories

Why fish oils work swimmingly against diabetes

Sep 02, 2010

Researchers at the University of California, San Diego School of Medicine have identified the molecular mechanism that makes omega-3 fatty acids so effective in reducing chronic inflammation and insulin resistance.

Killing 'angry' immune cells in fat could fight diabetes

Oct 07, 2008

By killing off "angry" immune cells that take up residence in obese fat and muscle tissue, researchers have shown that they can rapidly reverse insulin resistance in obese mice. The findings reported in the October Cell Me ...

Diabetes weakens your bones

Sep 28, 2009

Current research suggests that the inflammatory molecule TNF-α may contribute to delayed bone fracture healing in diabetics. The related report by Alblowi et al, "High Levels of TNF-α Contribute to Accelerated ...

Lung cancer cells activate inflammation to induce metastasis

Dec 31, 2008

A research team from the University of California, San Diego School of Medicine has identified a protein produced by cancerous lung epithelial cells that enhances metastasis by stimulating the activity of inflammatory cells. ...

Recommended for you

Leeches help save woman's ear after pit bull mauling

2 hours ago

(HealthDay)—A pit bull attack in July 2013 left a 19-year-old woman with her left ear ripped from her head, leaving an open wound. After preserving the ear, the surgical team started with a reconnection ...

New pain relief targets discovered

14 hours ago

Scientists have identified new pain relief targets that could be used to provide relief from chemotherapy-induced pain. BBSRC-funded researchers at King's College London made the discovery when researching ...

Building 'smart' cell-based therapies

14 hours ago

A Northwestern University synthetic biology team has created a new technology for modifying human cells to create programmable therapeutics that could travel the body and selectively target cancer and other ...

User comments : 0

More news stories

Leeches help save woman's ear after pit bull mauling

(HealthDay)—A pit bull attack in July 2013 left a 19-year-old woman with her left ear ripped from her head, leaving an open wound. After preserving the ear, the surgical team started with a reconnection ...

Male monkey filmed caring for dying mate (w/ Video)

(Phys.org) —The incident was captured by Dr Bruna Bezerra and colleagues in the Atlantic Forest in the Northeast of Brazil.  Dr Bezerra is a Research Associate at the University of Bristol and a Professor ...

Scientists tether lionfish to Cayman reefs

Research done by U.S. scientists in the Cayman Islands suggests that native predators can be trained to gobble up invasive lionfish that colonize regional reefs and voraciously prey on juvenile marine creatures.