Study offers new insight into powerful inflammatory regulator

May 1, 2017
University of Illinois biochemistry professor Lin-Feng Chen, right, with, from left, postdoctoral researchers Xiangming Hu, Yan Bao and Jinjing Chen, study proteins that regulate the inflammatory response. Credit: L. Brian Stauffer

A new study in mice reveals how a protein called Brd4 boosts the inflammatory response—for better and for worse, depending on the ailment. The study is the first to show that this protein, while problematic in some circumstances, also can protect the body from infection. The findings are reported in the Proceedings of the National Academy of Sciences.

The heat, swelling, redness and pain associated with are evidence that the immune system is working to protect the body. Once its job is complete, the normally recedes and disappears.

Sometimes inflammation fails to stop, and instead turns against the body, attacking healthy tissues and leading to chronic such as asthma, arthritis, diabetes and cancer.

One very powerful protein complex, called NF-kappaB, influences the expression of numerous genes and governs both beneficial and harmful inflammatory responses. When NF-kappaB regulates discriminately, the body heals and survives. When NF-kappaB overreacts, inflammation can become dangerous.

The NF-kappaB protein is a primary target for research looking for a way to stop inflammatory diseases.

The new study, led by University of Illinois biochemistry professor Lin-Feng Chen , reveals how Brd4 influences NF-kappaB and contributes to inflammation.

"Brd4 acts like a turboboost for the NF-kappaB protein that regulates inflammation. For NF-kappaB to be 100 percent productive, it needs the help from Brd4," Chen said.

Earlier work in Chen's lab revealed that Brd4 attaches to the NF-kappaB protein by recognizing a chemical tag. If Brd4 or the tag is not present, the potential of NF-kappaB protein to act as inflammation regulator is compromised.

The new study in mice confirmed that Brd4 plays a major role in acute . The researchers deleted the mouse Brd4 gene in certain types of immune cells, including macrophages, and monitored the of these mice. Many of the NF-kappaB-dependent, inflammation-related genes involved in fighting infection were down-regulated in Brd4-deficient macrophages.

"We found that in the absence of Brd4, the immune system of mice was compromised. They were more resistant to a massive immune response, but more susceptible to bacterial infection," Chen said.

"Cancers and some inflammatory diseases use Brd4 to boost the expression of that lead to the growth or persistence of the disease, but Brd4 has the same effect on inflammation that is needed to kill bacteria and viruses," he said.

The researchers also discovered a new mechanism for the reduced inflammatory gene expression in cells lacking Brd4. They found that deletion of Brd4 enhanced the protein synthesis of a NF-kappaB inhibitor, preventing the NF-kappaB from stimulating inflammatory gene expression.

"The next step is to test whether the absence of the gene for Brd4 would weaken the strength of the NF-kappaB - and inhibit - without compromising the body's ability to fight off bacteria and viruses," Chen said.

"Pharmaceutical companies are currently investing enormous resources - to the tune of hundreds of millions of dollars - seeking molecules that will inhibit the Brd4," Chen said. "Our findings urge caution and further foundational research before treatments involving the inhibition of Brd4 are used on patients."

Explore further: Protein that switches cancers from inflammation to proliferation identified

More information: Yan Bao el al., "Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1700109114

Related Stories

Protein that switches cancers from inflammation to proliferation identified

February 5, 2016
Oxford University scientists researching PAD4, a protein that plays a role in the development of inflammatory diseases like arthritis and which is regularly found in cancers have uncovered the protein's role in cancer development. ...

Researchers identify protein required for breast cancer metastasis

November 15, 2016
Researchers have identified a new pathway and with it a protein, BRD4, necessary for breast cancer cells to spread.

Team finds mechanism linking key inflammatory marker to cancer

May 20, 2013
In a new study described in the journal Oncogene, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumor growth.

Unexpected protein partnership has implications for cancer treatment

April 15, 2014
Scientists have identified two unlikely partners, in a type of immune cell called a macrophage, that work together, in response to cancer drugs, to increase inflammation in a way that may alter tumor growth. Researchers from ...

Ischemic renal failure and organ damage: A new mouse model holds the key

January 28, 2016
Every year acute renal failure affects over 13 million people and leads to 1.7 million deaths across the globe.It often develops when an insufficient supply of oxygen reaches the kidneys, a condition called ischemia. Working ...

Recommended for you

New compound discovered in fight against inflammatory disease

September 22, 2017
A 10-year study by University of Manchester scientists for a new chemical compound that is able to block a key component in inflammatory illness has ended in success.

Asthma researchers test substance from coralberry leaves

September 14, 2017
The coralberry could offer new hope for asthmatics. Researchers at the University of Bonn have extracted an active pharmaceutical ingredient from its leaves to combat asthma, a widespread respiratory disease. In mice, it ...

Respiratory experts urge rethink of 'outdated' asthma categorisation

September 12, 2017
A group of respiratory medicine experts have called for an overhaul of how asthma and other airways diseases are categorised and treated.

New 'biologic' drug may help severe asthma

September 7, 2017
(HealthDay)—A "biologic" drug in development to treat severe asthma reduces the rate of serious attacks by about two-thirds compared to a placebo drug, according to preliminary research findings.

Songbird study shows how estrogen may stop infection-induced brain inflammation

August 31, 2017
The chemical best-known as a female reproductive hormone—estrogen—could help fight off neurodegenerative conditions and diseases in the future. Now, new research by American University neuroscience Professor Colin Saldanha ...

New insights into protein's role in inflammatory response

July 28, 2017
A protein called POP2 inhibits a key inflammatory pathway, calming the body's inflammatory response before it can become destructive, Northwestern Medicine scientists have demonstrated in mouse models.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.