Hitting inflammation in the guts

November 6, 2013
Infiltrating fibroblasts (green) in a model of inflammatory bowel disease

Researchers in UCD Conway Institute and Systems Biology Ireland have identified a way that a new class of anti-inflammatory drugs may be used to treat inflammatory bowel disease (IBD).

IBD describes a group of commonly occurring and severe diseases including Crohn's disease and ulcerative colitis. Treatment options for the hallmark symptom of chronically inflamed intestinal tissues are limited, often ultimately requiring surgical removal of inflamed tissue.

A research team led by Professor Cormac Taylor, UCD Conway Institute, have previously shown that a class of drugs called hydroxylase inhibitors may provide a new approach to the treatment of IBD. This study now outlines how this occurs at the molecular level.

Hypoxia is a key microenvironmental feature of inflamed tissues that strongly impacts on the inflammatory processes. A family of oxygen-sensing enzymes called HIF-hydroxylases are responsible for controlling the cellular adaptive response to hypoxia.

This new study, led by Prof Cormac Taylor, Dr Eoin Cummins and Dr Carsten Scholz and published in the Proceedings of the National Academy of Sciences, show that hydroxylase inhibitors work by blocking a pro-inflammatory pathway termed the IL-1 pathway; a key driver of inflammation.

These results give significant new information as to a new level of crosstalk between hypoxia and inflammation and provide a mechanism to explain how this new approach to the control of inflammation may work.

Outlining the results, Dr Eoin Cummins said, "We demonstrate that pharmacologic hydroxylase inhibition down-regulates IL-1b-induced pro-inflammatory NF-kB activity both in vitro and in vivo. Two distinct hydroxylase isoforms, PHD1 and FIH, are acting together to achieve this inhibitory effect, which occurs downstream of TRAF6 activation.

A number of key proteins in the proximal IL-1b signalling pathway were found to interact with PHD1 and FIH and/or be subject to hydroxylation. Based on this data, we hypothesise a key role for hydroxylation as a new post-transcriptional modification in the IL-1b pathway."

"This research stems from studies in our laboratory over the last decade into how cells respond to decreased . We found that cells can adapt to low oxygen levels much like mountain climbers adapt to low oxygen levels at altitude. If we use drugs to mimic this adaptive response in inflammation, it suppresses the inflammatory response" says Professor Taylor.

Explore further: A new 'on' signal for inflammation

More information: Regulation of IL-1β–induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways. Carsten C. Scholz, Miguel A. S. Cavadas, Murtaza M. Tambuwala, Emily Hams, Javier Rodríguez, Alex von Kriegsheim, Philip Cotter, Ulrike Bruning, Padraic G. Fallon, Alex Cheong, Eoin P. Cummins, and Cormac T. Taylor. PNAS 2013 ; published ahead of print October 21, 2013, DOI: 10.1073/pnas.1309718110

Related Stories

A new 'on' signal for inflammation

May 14, 2013
(Medical Xpress)—Inflammation is an important response in the body - it helps you to kill off invaders such bacteria that could cause a harmful infection. But if it's chronic or uncontrolled, inflammation can also cause ...

Opening up new pathways for treating inflammatory bowel diseases

August 12, 2013
Inflammatory bowel disease (IBD) is a chronic condition affecting 1 in 250 people in Europe. Current treatment is ineffective for many. However, a team of European scientists has increased understanding of the causes of IBD, ...

Illuminating cross talk between signalling factors

November 22, 2011
(Medical Xpress) -- Hypoxia and inflammation are environmental features occuring simultaneously in a variety of diseases such as growing tumours and critically inflamed tissues. UCD scientists investigating the relative contributions ...

Research shows genetic anti-inflammatory defect predisposes children to lymphoma

October 2, 2013
New research shows that children with an inherited genetic defect in a critical anti-inflammatory pathway have a genetic predisposition to lymphoma. Results of the study, published online today in Blood, the Journal of the ...

Scientists uncover protective influence of Vitamin A against inflammatory bowel disease

June 5, 2013
Scientists at Trinity College Dublin have made novel discoveries around the protective influence of Vitamin A against the damaging immune responses that lead to inflammatory bowel disease. The research led by Professor of ...

Recommended for you

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

New vaccine production could improve flu shot accuracy

July 24, 2017
A new way of producing the seasonal flu vaccine could speed up the process and provide better protection against infection.

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

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.