Three potent proteins of the immune system, evolved to purge us of intestinal parasites, now often launch misguided attacks in our airways, triggering the congestion of asthma that leaves millions gasping for air.
By studying the genetic machinery that controls production of these immune soldiers called cytokines, a team of scientists has demonstrated a potential strategy to silence their misfiring and quell the asthma response.

In back-to-back papers, researchers at UC Scan Francisco and the Lawrence Berkeley National Laboratory (LBL) report that a stretch of DNA controlling all three cytokine genes is so similar in humans and mice that the mouse DNA can active the three human genes inserted in a mouse.

The researchers showed too that the activity of all three genes can be at least partially blocked, suggesting that a single drug could be used to attack asthma at its genetic source. Such a drug could be reliably tested in mice, their study shows.

"The primary aim of our research has been to demonstrate that if non-coding regions of DNA (stretches containing no genes) have been conserved in species separated by many millions of years, they probably perform vital functions," said Richard

 Locksley, MD, Investigator in the Howard Hughes Medical Institute and professor of medicine and microbiology/immunology at UCSF.

       "But in choosing a DNA region that modulates the genes for the cytokines IL-4, 5 and 13, we are dealing with genes that are dramatically expressed in asthma and other allergic diseases. Our experiments show that all three genes are regulated by the same non-coding DNA region, and interruption of this control affects all three genes at once. By blocking the activity of this region, we should be able to block the expression of all three genes."
Many drugs are now being designed to interfere with activity of a single gene or the protein coded by that gene, but developing a drug to treat a disease caused by at least three genes could be far more difficult, Locksley said. Targeting a region of the genome that controls expression of the three genes at once may offer a solution.

      The demonstration that the human genes for IL-4, 5 and 13 can be faithfully expressed in mice under the regulation of the mouse DNA is being published in Journal of Immunology.

       The publication comes a few weeks after the team, led by the LBL scientists, identified the high degree of similarity between the mouse and human stretches of DNA

 that regulate expression of the genes. These findings were published in the April issue of the journal Science.

       Over the past decade a powerful principle has emerged that genes shared by evolutionarily distant species are likely to play major roles for the organisms and may provide a window to understanding basic genetic mechanisms. The research by the UCSF/LBL team extends that principle to the non-gene portions of the genome.

      In the research reported in the Journal of Immunology, scientists inserted human chromosome segment 5q31 which contains the genes for the three human interleukins (Ils) into the chromosome of a mouse that include that species' versions of these genes.
       "Remarkably," they report, "these human Ils were expressed faithfully in CD4+T cells in vitro and in vivo. These data support the existence of conserved regulatory elements near the cytokine cluster itself that enables the activation and/or stable expression of the type 2 cytokine genes in a cell and lineage-specific manner."

       The resulting transgenic mouse strains showed normal lymph system development. However, the mice did develop fewer mouse IL-4- producing cells, suggesting competition exists between the mouse and human: cytokines genes for expression in the transgenic mice.