Featured Research

from universities, journals, and other organizations

Study identifies novel role for a protein that could lead to new treatments for rheumatoid arthritis

Date:
May 23, 2011
Source:
Hospital for Special Surgery
Summary:
A new study by rheumatologists has shown that a powerful pro-inflammatory protein, tumor necrosis factor, can also suppress aspects of inflammation. The researchers say the identification of the mechanism of how this occurs could potentially lead to new treatments for diseases such as rheumatoid arthritis.

A new study by rheumatologists at Hospital for Special Surgery in New York has shown that a powerful pro-inflammatory protein, tumor necrosis factor (TNF), can also suppress aspects of inflammation. The researchers say the identification of the mechanism of how this occurs could potentially lead to new treatments for diseases such as rheumatoid arthritis. The study was published May 22 online in advance of publication in the journal Nature Immunology.

"Prior to this study, TNF has long been known as a potent pro-inflammatory cytokine, but if you look carefully through the literature, there are hints that it also has some suppressive functions, but nothing was known about the mechanisms," said Lionel Ivashkiv, M.D., associate chief scientific officer and physician in the Arthritis and Tissue Degeneration Program at Hospital for Special Surgery who led the study. "This is really the first mechanism showing how TNF can turn inflammation down."

Because many proteins have homeostatic functions, both driving and suppressing certain actions so a cell can maintain internal equilibrium, researchers thought TNF might not be an exception. "Most strong activators in the immune system trigger a feedback response to restrain the amount of inflammation," Dr. Ivashkiv said.

To find out, researchers designed experiments stimulating macrophages with lipopolysaccharide (LPS), a prototypical inflammatory factor that stimulates receptors important in inflammation. In test tube studies, the researchers treated human monocytes and macrophages, cells that have a key role in inflammatory diseases, with TNF and then challenged these cells with LPS. They found that the TNF suppressed the inflammatory response of the macrophages and monocytes. They then gave mice low doses of TNF followed by high doses of LPS and found that the mice were protected from the effects of high dose LPS, which is usually lethal. They discovered that the mechanism by which TNF suppressed the inflammatory response involved a protein known as GSK3 (glycogen synthase kinase 3-alpha) and a gene known as TNFAIP3 that encodes the A20 protein. Experiments with a drug that can inhibit GSK3 as well as experiments with RNA interference of A20, which can block A20 gene function, helped identify the roles of this protein and gene.

The researchers say the findings could be used to develop potential therapies for diseases, such as rheumatoid arthritis. "We think it is relevant to rheumatoid arthritis, not only because the cells we are studying (the macrophages) are exactly the same cells that migrate into joints and make the inflammatory cytokines involved in rheumatoid arthritis, but because A20 is involved. TNFAIP3 is one of the best linked genes to rheumatoid arthritis," Dr. Ivashkiv said. "There are polymorphisms in the A20 gene that have been linked to RA pathogenesis."

The researchers hypothesize that patients who make less A20 are more susceptible to inflammation and thus rheumatoid arthritis. One approach to treating RA could be to increase A20 levels in patients who naturally make less A20 by manipulating GSK-3, since this study showed that GSK-3 influences A20. "The study sort of opens a line of investigation to understanding how A20 levels can be manipulated in patients with various diseases," Dr. Ivashkiv said.

The findings could be applied to other diseases besides arthritis. In conditions such as rheumatoid arthritis, you may want to boost A20, but in other settings such as cancer, where the macrophages are suppressed, you may want to inhibit A20 expression.

"What the study shows that is new is that TNF has suppressive functions in addition to its well-known activating functions," Dr. Ivashkiv said. "Before this study, people thought it might suppress adaptive immunity, but surprisingly we found that it actually suppresses a cell of the innate immune system, the macrophage, which is the same cell that makes it and, by doing that, it regulates its own production."


Story Source:

The above story is based on materials provided by Hospital for Special Surgery. Note: Materials may be edited for content and length.


Journal Reference:

  1. Sung Ho Park, Kyung-Hyun Park-Min, Janice Chen, Xiaoyu Hu, Lionel B Ivashkiv. Tumor necrosis factor induces GSK3 kinase–mediated cross-tolerance to endotoxin in macrophages. Nature Immunology, 2011; DOI: 10.1038/ni.2043

Cite This Page:

Hospital for Special Surgery. "Study identifies novel role for a protein that could lead to new treatments for rheumatoid arthritis." ScienceDaily. ScienceDaily, 23 May 2011. <www.sciencedaily.com/releases/2011/05/110522141600.htm>.
Hospital for Special Surgery. (2011, May 23). Study identifies novel role for a protein that could lead to new treatments for rheumatoid arthritis. ScienceDaily. Retrieved September 16, 2014 from www.sciencedaily.com/releases/2011/05/110522141600.htm
Hospital for Special Surgery. "Study identifies novel role for a protein that could lead to new treatments for rheumatoid arthritis." ScienceDaily. www.sciencedaily.com/releases/2011/05/110522141600.htm (accessed September 16, 2014).

Share This



More Health & Medicine News

Tuesday, September 16, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

President To Send 3,000 Military Personnel To Fight Ebola

President To Send 3,000 Military Personnel To Fight Ebola

Newsy (Sep. 16, 2014) President Obama is expected to send 3,000 troops to West Africa as part of the effort to contain Ebola's spread. Video provided by Newsy
Powered by NewsLook.com
Man Floats for 31 Hours in Gulf Waters

Man Floats for 31 Hours in Gulf Waters

AP (Sep. 16, 2014) A Texas man is lucky to be alive after he and three others floated for more than a day in the Gulf of Mexico when their boat sank during a fishing trip. (Sept. 16) Video provided by AP
Powered by NewsLook.com
Ivorians Abandon Monkey Pets in Fear Over Ebola Virus

Ivorians Abandon Monkey Pets in Fear Over Ebola Virus

AFP (Sep. 16, 2014) Since the arrival of Ebola in Ivory Coast, Ivorians have been abandoning their pets, particularly monkeys, in the fear that they may transmit the virus. Duration: 00:47 Video provided by AFP
Powered by NewsLook.com
Study Links Male-Pattern Baldness To Prostate Cancer

Study Links Male-Pattern Baldness To Prostate Cancer

Newsy (Sep. 16, 2014) New findings suggest men with a certain type of baldness at age 45 are 39 percent more likely to develop aggressive prostate cancer. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

    Technology News



    Save/Print:
    Share:

    Free Subscriptions


    Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

    Get Social & Mobile


    Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

    Have Feedback?


    Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
    Mobile: iPhone Android Web
    Follow: Facebook Twitter Google+
    Subscribe: RSS Feeds Email Newsletters
    Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins