Little-known substance regulates inflammatory response

September 28, 2000

In the September 29 issue of the journal Science, researchers from the University of Chicago show that a little-known molecule called A20 plays a critical role in regulating inflammation. This unexpected finding suggests an entirely new target for drugs designed to treat inflammatory diseases such as ulcerative colitis, Crohn's disease, rheumatoid arthritis and even septic shock.

First discovered ten years ago, A20 was largely ignored as an insignificant link in the chain reaction of inflammation. Scientists thought it was only produced by certain types of white blood cells in a few tissues such as the intestines and thymus.

"A20 had been studied in only a limited way at the cellular level and never in a live animal," said Averil Ma, M.D., assistant professor of medicine and immunology at the University of Chicago, who uses transgenic mice to study the basic biology of inflammatory bowel disease.

"We created mice that lacked the A20 gene, hoping to identify its function in intestinal lymphocytes," he said. Instead they discovered that the molecule was much more widespread than anticipated and that it was a critical regulator of inflammation in multiple tissues.

"We found that rapid expression of A20," said Ma, "was absolutely essential for down-regulating the inflammatory response and averting the damage unrestrained inflammation can cause in multiple tissues."

Within three to six weeks after birth, mice without the gene for A20 spontaneously developed severe inflammation and tissue damage in multiple organs. When exposed to substances that mimic infection or trigger inflammation, mice lacking A20 developed symptoms identical to septic shock -- plummeting blood pressure, widespread inflammation, kidney damage, decreased heart function -- and died within two hours. In contrast, normal mice with A20 had no symptoms despite exposure to ten-fold higher doses of these same stimulants.

Inflammation is part of the normal response to an infection or injury. When it detects an invader such as bacteria or a virus, the immune system mobilizes urgently to repel the assailants. Immune system cells attack the intruders directly while releasing chemical signals to call in additional troops.

One of those signals is a substance known as tumor necrosis factor, or TNF. TNF not only initiates a cascade of other chemical messengers but also increases blood-vessel permeability, allowing white blood cells to pass easily out of the capillaries to reach the site of an infection.

Once the immune system gains the upper hand, however, it has to scale back this inflammatory response. Inflammation may be a valuable short-term weapon against infection, but prolonged inflammation can cause extensive damage to affected tissues by interfering with normal cellular processes, altering blood flow through the area, and triggering the death of affected cells.

High levels or prolonged release of TNF can lead to systemic problems, including widespread loss of fluid from distended and leaky blood vessels. This can cause the dramatic drop in blood pressure seen in septic shock, which can in turn damage the kidneys, lungs and heart and even cause death.

The researchers found that mice without the A20 gene were unable to limit the inflammatory process. When normal mice were exposed to TNF, all tissues studied (liver, kidney, spleen, thymus, colon and lymph nodes) produced large amounts of A20 and the mice survived unharmed.

Ma and colleagues were able to show that rapid production of A20 protected mice from the damaging effects of TNF by inhibiting that substance's ability to activate a protein within cells known as nuclear factor KB. NF-KB, in turn, regulates the production of other proinflammatory genes. In the absense of A20, unregulated NF-KB activity leads to inflammation, programmed cell death, and widespread tissue damage.

In addition to discovering a key step in regulating inflammatory processes, these studies may translate into novel forms of therapy. Antibodies to TNF have received FDA approval for treating inflammatory disorders such as ulcerative colitis, Crohn's disease and arthritis.

However, "these therapies are not always effective," said Ma. "Our recognition of the critical role of A20 terminating NF-KB-mediated inflammatory responses to TNF suggests new ways to block inflammation," he added. "We can now hope to block cellular responses to TNF, in addition to trying to block TNF itself."
-end-
Additional authors of the paper were Eric Lee, David Boone, Sophia Chai, Shon Libby, Marcia Chien and James Lodolce from the department of medicine at the University of Chicago. The National Institutes of Health, the Crohn's and Colitis Foundation of America, the Mr. and Mrs. Arthur Edelstein facility, the Martin Boyer Genetics Laboratories and the Gastrointestinal Research Foundation funded the research.

University of Chicago Medical Center

Related Blood Pressure Articles from Brightsurf:

Children who take steroids at increased risk for diabetes, high blood pressure, blood clots
Children who take oral steroids to treat asthma or autoimmune diseases have an increased risk of diabetes, high blood pressure, and blood clots, according to Rutgers researchers.

High blood pressure treatment linked to less risk for drop in blood pressure upon standing
Treatment to lower blood pressure did not increase and may decrease the risk of extreme drops in blood pressure upon standing from a sitting position.

Changes in blood pressure control over 2 decades among US adults with high blood pressure
National survey data were used to examine how blood pressure control changed overall among U.S. adults with high blood pressure between 1999-2000 and 2017-2018 and by age, race, insurance type and access to health care.

Transient increase in blood pressure promotes some blood vessel growth
Blood vessels are the body's transportation system, carrying oxygen and nutrients to cells and whisking away waste.

Effect of reducing blood pressure medications on blood pressure control in older adults
Whether the amount of blood pressure medications taken by older adults could be reduced safely and without a significant change in short-term blood pressure control was the objective of this randomized clinical trial that included 534 adults 80 and older.

Brain blood flow sensor discovery could aid treatments for high blood pressure & dementia
A study led by researchers at UCL has discovered the mechanism that allows the brain to monitor its own blood supply, a finding in rats which may help to find new treatments for human conditions including hypertension (high blood pressure) and dementia.

Here's something that will raise your blood pressure
The apelin receptor (APJ) has been presumed to play an important role in the contraction of blood vessels involved in blood pressure regulation.

New strategy for treating high blood pressure
The key to treating blood pressure might lie in people who are 'resistant' to developing high blood pressure even when they eat high salt diets, shows new research published today in Experimental Physiology.

Arm cuff blood pressure measurements may fall short for predicting heart disease risk in some people with resistant high blood pressure
A measurement of central blood pressure in people with difficult-to-treat high blood pressure could help reduce risk of heart disease better than traditional arm cuff readings for some patients, according to preliminary research presented at the American Heart Association's Hypertension 2019 Scientific Sessions.

Heating pads may lower blood pressure in people with high blood pressure when lying down
In people with supine hypertension due to autonomic failure, a condition that increases blood pressure when lying down, overnight heat therapy significantly decreased systolic blood pressure compared to a placebo.

Read More: Blood Pressure News and Blood Pressure Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.