A Jekyll and Hyde of Cytokines: IL-25 Both Promotes and Limits Inflammatory Diseases

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A Jekyll and Hyde of Cytokines: IL-25 Both Promotes and Limits

Inflammatory Diseases

April 10, 2006

The same signal responsible for promoting the type of immune

responses that cause asthma and allergy can also limit the type of

inflammation associated with debilitating diseases like inflammatory

bowel disease, arthritis and multiple sclerosis, according to

researchers from the University of Pennsylvania School of Veterinary

Medicine. The researchers discovered how IL-25, a signaling protein

known as a cytokine, both prevents destructive inflammation and

promotes immune responses associated with asthma and allergic responses.

The findings, which appear the April issue of the Journal of

Experimental Medicine, suggest that manipulating IL-25 could provide

a method to treat a wide variety of chronic inflammatory diseases.

" It appears that IL-25 has a Jekyll and Hyde personality: it can be

helpful or hurtful depending on how it interacts with T helper cells,

a subset of immune cells that influences inflammatory responses, "

said Artis, an assistant professor in Penn's Department of

Pathobiology and senior author of the study. " These studies show

that IL-25 promotes type 2 T helper cells that drive the type of

response required for eradicating worm infections and causing

asthma. Importantly, IL-25 can simultaneously limit destructive

inflammation caused by inflammatory T helper cells commonly found in

diseases like inflammatory bowel disease, arthritis and MS. "

IL-25 can be considered a oodcytokine by limiting chronic

inflammatory responses. At the same time, the ability of IL-25 to

promote type 2 responses that drive asthma could be considered the

vilside of the cytokine.

By examining mice infected with Trichuris, a species of intestinal

parasites known as whipworms, the researchers were able to define

IL-25's role in promoting type 2 inflammation to fight infection. In

mice that lack the ability to produce IL-25, researchers saw a

dramatic reduction in the ability to mount a type 2 response that

eradicates the parasites. Furthermore, in the absence of IL-25, mice

developed a destructive inflammatory response similar to that

observed in models of inflammatory bowel disease.

These results also support the notion that the immune response that

causes allergies and asthma is an evolutionary hangover resulting

from mankind's historical fight with parasitic worm infections. That

is, a type 2 response that was once useful in fighting worm

infections has now become a dangerous menace, causing inflammatory

responses to commonly encountered environmental antigens. About 30

percent of Americans suffer from the negative affects of type 2

inflammation: asthma and allergies. These conditions result from an

inflammatory response to factors encountered in the environment,

whether they are industrial air pollutants or molecules of peanut oil.

" It is possible that for most of human history, cytokines like IL-25

have promoted type 2 T helper cells that fight infection with

intestinal parasites like Trichuris, " said Colby Zaph, a co-author

and Irvington Research Fellow at Penn. " In industrialized countries,

where worm infections are now rare, this redundant type 2 response is

associated with diseases like asthma. "

" Identifying a role for IL-25 in this type of response may offer an

exciting new avenue for treating diseases associated with

dysregulated inflammatory responses, " Zaph said.

Researchers involved in this report include Colby Zaph, Emma H.

, J. Guild, A. Hunter and Artis

from Penn; Hugh R. P. from the University of Edinburgh; and

M. Owyang, Terrill McClanahan, J. Cua and A.

Kastelein from Schering-Plough Biopharma.

Funding for this research was provided by the National Institutes of

Health, The Crohn's and Colitis Foundation of America's

Shelby Modell Family Foundation Research Award, the Irvington

Institute for Immunological Research and Schering-Plough Biopharma.

http://www.upenn.edu/pennnews/article.php?id=942

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