Engineered Molecule Amplifies Body's Immune Response

Stat1 is involved in immune responses that are initiated by proteinscalled interferons. These proteins are produced by the cells of theimmune system in response to challenges by foreign agents such asviruses, bacteria, parasites and tumor cells. Recently, interferon hasalso been shown to play a role in the body's surveillance against thedevelopment of cancer. Because of this role, recombinant interferon isoften used for the treatment of certain fibrotic diseases as well ascancers.

Interferon binds to receptors on the surface of the cell, which thenuse Stat molecules to send signals to the nucleus to increase theexpression of genes needed to defend the host against infection. Abalance in the amount of Stat signaling caused by interferon is veryimportant.

"When interferon levels are too low, the host is highly susceptible toinfection," explains Dr. Michael J. Holtzman of the WashingtonUniversity School of Medicine in St. Louis, Missouri. "This alsoapplies to Stat1. Children who are born with genetic deficiencies ofStat1 are also very susceptible to infection. In the more severe case,the children die in infancy of fatal viral infections. In less severecases, they later develop infections due to mycobacteria. Wheninterferon levels are too high, for example during treatment withinterferon, there are side effects due to the increased nonspecificresponse caused by excessive amounts of interferon."

Dr. Holtzman and his colleagues at the Washington UniversitySchool of Medicine decided to try to improve the body's defense againstinfection without causing side effects that occur with interferontreatment by engineering a hyper-responsive Stat1 molecule. Byincreasing the efficiency of the Stat1 molecule, the host could havethe benefits of increased Stat1 signaling even at the low levels ofinterferon normally present in the body. Their results appear as the"Paper of the Week" in the October 7 issue of the Journal of BiologicalChemistry, an American Society for Biochemistry and Molecular Biologyjournal.

"Our paper is really quite simple in conceptual terms," says Dr.Holtzman. "It is well known that interferon provides a benefit topeople by protecting them against infectious diseases and cancer.Unfortunately, administration of interferon is costly and short-livedand has significant side effects. We simply reasoned that it might bepossible to improve the benefits of interferon by enhancing the way itproduces its beneficial effects. We therefore improved a molecule,known as Stat1, that is responsible for relaying the benefits ofinterferon in the body."

Their initial in vitro results were promising, and the engineered Stat1molecule exhibited an increased responsiveness to interferon. Followingup on these discoveries, Dr. Holtzman and his colleagues are currentlyperforming gene transfer experiments, using both recombinant virusesand transgenic mice, to establish the benefits of hyper-responsiveStat1 in vivo for treating viral infection and cancer. They are alsoscreening for drugs that might increase Stat1 responsiveness.

These experiments may eventually lead to many improvements in cancertherapy as well as the treatment of other infections. Basically, anysituation in which interferon hyper-responsiveness might be beneficialwill profit from Dr. Holtzman's research.

"One could use our strategy of improving Stat1 efficiency during thewinter months in patients who are at risk for developing serious viralinfections, for example children with asthma, or heart disease, orimmune compromise," suggests Dr. Holtzman. "It may also be of benefitin situations where interferon therapy has been used, such astreatments for liver disease and lung fibrosis, as well as certaincancers. Improving Stat1 efficiency would allow for much lower doses ofinterferon to be used, decreasing cost and side effect profile. Interms of diagnosis, it may be possible to screen patients for the levelof Stat1 responsiveness to interferon, and if found to be low, thatwould make them candidates for a strategy to improve Stat1responsiveness using our methods."

The Journal of Biological Chemistry's Papers of the Week is an onlinefeature which highlights the top one percent of papers received by thejournal. Brief summaries of the papers and explanations of why theywere selected for this honor can be accessed directly from the homepage of the Journal of Biological Chemistry online at www.jbc.org.

The American Society for Biochemistry and Molecular Biology (ASBMB) isa nonprofit scientific and educational organization with over 11,000members in the United States and internationally. Most members teachand conduct research at colleges and universities. Others conductresearch in various government laboratories, nonprofit researchinstitutions, and industry.

Founded in 1906, the Society is based in Bethesda, Maryland, on thecampus of the Federation of American Societies for ExperimentalBiology. The Society's primary purpose is to advance the sciences ofbiochemistry and molecular biology through its publications, theJournal of Biological Chemistry, the Journal of Lipid Research,Molecular and Cellular Proteomics, and Biochemistry and MolecularBiology Education, and the holding of scientific meetings.

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