There are 18 or so interleukins listed in the medical dictionaries. A person with chronic asthma doesn't have to be superstitious to react to the news that interleukin-13 plays a sinister role in that respiratory disease.

"There's quite a lot of morbidity from asthma," observed clinical and research pulmonary immunologist David Erle. "It's a major cause of lost work days and lost school days, because chronic asthma is very common in children as well as adults. And because the prevalence of asthma is so high - in the neighborhood of 10 percent," he continued, "it's a major cause of morbidity, and also a significant cause of mortality. People do die from asthma - on the order of 5,000 asthmatics a year in the U.S." (See BioWorld Today, March 20, 2002, p. 1.)

Erle, who combines research and medical practice at the University of California at San Francisco, is senior author of a paper in Nature Medicine, released online July 1, 2002. Its title: "Direct effects of interleukin-13 [IL-13] on epithelial cells cause airway hyperactivity and mucus overproduction in asthma."

"Our overall finding is that the epithelial cells - a major cell type that lines the airways - can play a central role in the way the lung responds to IL-13," Erle told BioWorld Today. "We also found that there can be dissociation between two of the critical features of asthma, airway hyperactivity and mucus production, and other pathologies, including emphysema, fibrosis and inflammation.

"What's novel about this work," he continued, "is how the IL-13 cytokine is inducing asthma pathology in lung epithelia. What's novel," he added, "is that we have shown that just one cell type - the epithelium - can be adequate to cause two of the most important features of asthma, the airway hyper-responses and mucus overproduction. IL-13 is normally produced in large quantities in the airways of people with asthma, but not in non-asthmatics. And the cells that are producing IL-13 appear to be mostly T lymphocytes of the immune system, as well as eosinophils and mast cells."

To suggest IL-13's possible useful function in people without asthma, Erle noted that "mice lacking IL-13 are basically normal under situations in which we keep them in mouse colonies. There are some differences in the way that they respond, for example, to allergens [the triggers of asthma attacks] and to parasitic infections. So it's possible that nature evolved a system to help humans fight parasitic infections. Now in some developed countries where there are not a lot of parasitic infections, some of these defense mechanisms turn out to be involved in the pathogenesis of allergic disease."

Now Meet Transcription Factor STAT6

IL-13's tango partner is a molecule called STAT6, short for "signal transducer and activator of transcription 6."

"In the normal human body," Erle observed, "STAT6 is involved in signaling in response to both IL-13 and IL-4. This is a closely related cytokine that in some cases uses the same receptors as IL-13. So both IL-4 and IL-13 activate STAT6, and cause expression of a variety of genes in response to this activation. There are not very many other molecules besides IL-4 and IL-13 that signal to STAT6," Erle pointed out. "So I think one could hope that targeting STAT6 itself is potentially a viable therapeutic strategy. STAT6-deficient mice survived and appeared to be normal adult animals until they were subjected to a situation where they had to develop an allergic response, or react to a parasite, for example. So it's not unreasonable to think that one could inactivate STAT6 for long periods of time, especially if it could be done selectively in certain cell types, like the epithelial cells in the lung, without having undue side effects."

Erle recounted his in vivo experiments: "We simply made mice that overexpressed IL-13, and had genetically manipulated STAT6 expression. We didn't treat those transgenic animals in any special way. We didn't expose them to allergens. We merely allowed them to reach an appropriate age for studying. Then we characterized them in a number of different ways. We measured their airway responsiveness in an assay that parallels the diagnostic test we do in humans whom we suspect might have asthma. That involves challenging them with two potent bronchoconstrictors, either acetylcholine [AC] or methacholine [MC]. AC can be given intravenously, MC by inhalation. That's what we usually give asthmatics. People with asthma have an exaggerated response to MC, so if we give them a very low dose of it, their airways narrow, and they start to wheeze. Whereas for a person without asthma you'd have to give much higher doses of MC to get that response.

"But those transgenic mice are the same way," Erle noted. "Those that overexpress IL-13 are hyper-responsive to MC and AC. The next thing we did was simply look at their lungs and see if there was mucus production. And again we observed that IL-13 induced a large amount of mucus. If the mice did not have STAT6 at all, that mucus went away. Then we showed that if we put STAT6 back, just in the epithelium, it returned to the same extent that we saw in mice with normal STAT6 expression."

Following Drug Discovery Pathway

"One idea," Erle went on, "is that we might be able to interrupt IL-13 acting on the epithelial cell and activating STAT6 - targeting that interaction, either by blocking IL-13 production, binding its receptor on the epithelium, or blocking activation of STAT6 itself in the lung. Those manipulations would possibly be done using inhaled therapy, which is delivered directly to the epithelium, rather than systemic therapy - by pill or needle - which raises more concerns about side effects.

"It's my understanding," Erle added, "that the pharmaceutical industry would like to find a small-molecule STAT6 inhibitor that worked orally, because of patient acceptance and ease of use. We are not developing that ourselves," he said, "but we would consider doing it if there seemed to be a good candidate compound worth testing. Right now, we're interested in identifying some of the specific genes that might be turned on by the activation of STAT6 in epithelial cells, and might lead to asthma's airway hyperactivity and mucus production."

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