NEWS: Protein's Role In Stopping Bacterial-Induced Inflammation

[Guest guest]

Source: University of California, San Diego Released: Mon

25-Apr-2005, 13:30 ET

Protein's Role In Stopping Bacterial-Induced Inflammation

Description

UCSD researchers have identified a key protein involved in the

appropriate shut-down of inflammation following an immune response to

invading pathogens.

Newswise — In findings that could have implications for autoimmune

disorders and drug-resistant bacterial infections, researchers at the

University of California, San Diego (UCSD) School of Medicine have

identified a key protein involved in the appropriate shut-down of

inflammation following an immune response to invading pathogens.

Published in the April 28, 2005 issue of the journal Nature, the study

in mice and lab cultures of immune cells called macrophages showed that

a protein called I-kappa-B kinase alpha (IKKa) is responsible for

terminating an inflammatory response before it can damage cells and

organs.

Senior author Karin, Ph.D., UCSD professor of pharmacology,

explained that IKKa is part of a sophisticated two-punch system that

maintains a proper inflammatory response. While it is well known that

IKKa’s sister protein, IKK beta (IKKb), initiates the inflammatory

response, little was known about the mechanism for stopping the

response before it injures tissue, such as the damage that occurs in

chronic bacterial and parasitic infections like tuberculosis and

leprosy, or in autoimmune disorders like rheumatoid arthritis, multiple

sclerosis, and systemic lupus erythematosus (SLE).

Karin’s team, which was the first to identify the IKK protein complex

in 1996, determined in this new investigation that both IKKa and IKKb

are activated at the same time following a microbial infection. While

IKKb initiates the inflammatory response by causing the degradation of

inhibitory proteins called IkBs, IKKa interacts with two additional

proteins – RelA and C-Rel – which move into the nucleus of the cell

after the IkBs are degraded. After being “tagged” by IKKa in the

cytoplasm of the cell, RelA and c-Rel bind to genes that mediate the

inflammatory response. But their life is limited – the IKKa-mediated

“tag” ensures that RelA and c-Rel will bind to their target genes for

only a short duration. Once RelA and c-Rel are removed from their

target genes, the inflammatory response is terminated.

“This is very important for a proper inflammatory response in infection

and immunity,” Karin said. “The inflammatory response involves the

production of potentially toxic mediators, so it is important that

inflammation be allowed to do its work rapidly, but only transiently.”

The new findings also have implications for disorders such as

flesh-eating staph infections and drug-resistant bacterial infections

that are difficult to treat. The researchers note that in these cases,

it might be possible to develop an inhibitor of IKKa that boosts the

inflammatory response to better fight these infections. However, such

an inhibitor should have a short half-life, so that its potential

devastating effect can be properly terminated.

The Karin lab, which has made several of the past discoveries involving

IKKb’s pro-inflammatory role, has also studied IKKa over the years, but

they have identified roles unrelated to the primary inflammatory

response. For example, in 2001, the investigators determined that IKKa

was essential for formation of the skin’s outer layer.* In a follow-up

study, the team found clues that IKKa may be more involved in the

immune response than they previously thought, but its role still

appeared limited.** The current study is the first, however, to

specifically show the novel mechanisms used by the protein to control

the duration of an inflammatory response.

The study was funded by the National Institutes of Health. The co-first

authors were Toby Lawrence, Ph.D., and Magali Bebien, Ph.D.,

post-doctoral fellows in the Laboratory of Gene Regulation and Signal

Transduction, UCSD Department of Pharmacology. Currently, Lawrence is

an assistant professor and member of the Faculty of Medicine, Imperial

College London. Additional authors were Liu, Ph.D., UCSD

Division of Pediatric Infectious Diseases, UCSD School of Medicine; and

Victor Nizet, M.D., associate professor of pediatrics, UCSD School of

Medicine.

a