Virginia Commonwealth University immunologists studying mastcells, known to play a central role in asthma and allergic disease,have identified a hormone-like molecule that can kill these cells byprogramming them to die in studies with mice.
The findings moveresearchers another step closer to understanding the life cycle of mastcells, and may help researchers develop new treatments for allergy andinflammatory responses in arthritis, multiple sclerosis and heartdisease.
In the Journal of Immunology, published online Aug. 23,researchers demonstrated the means by which a cytokine calledinterferon gamma (IFNy) induces death of developing mast cells in amouse model system. Although IFNy induced cell death in developing mastcells, it did not affect the survival of mast cells that had alreadyundergone differentiation.
“We believe that cytokines, such asinterferon gamma, are an important means of controlling mast cellfunction in the body,” said John J. Ryan, Ph.D., associate professor ofbiology at VCU and lead author of the study. “Because mast cells causeinflammation, regulating how many mast cells the body makes, where theygo, what they do, and when they die can have a huge impact on healthand disease.
“For example, there has been one report of apatient with mastocytosis, which is a type of pre-leukemia where mastcells proliferate abnormally, that showed improvement with IFNytreatment,” he said. “It is possible that other mast cell-relateddiseases, such as asthma, may respond to IFNy treatment.”
Accordingto Ryan, mast cells are packed with granules containing histamine andare present in nearly all tissues except blood. When mast cells areactivated, inflammatory substances such as histamine, heparin and anumber of cytokines are rapidly released into the tissues and blood,promoting an allergic reaction.
Mast cells are believed to begenerated by different precursor cells in the bone marrow. In the invitro portion of the study, researchers used mouse bone marrow cellscontaining the stem cells that give rise to mast cells. They culturedthese precursor cells in conditions that allow mast cells to develop,and then added IFNy to some of these cultures. A high rate of celldeath yielding no living mast cells was observed in the cultures thatreceived IFNy.
Similar results were reported in vivo using amouse model. Mice with a mutation that causes them to overproduce IFNywere used, and again, researchers observed a significant decrease inmast cell numbers due to the excess of IFNy. When researchers tried toculture mast cells from the bone marrow of these mice, the mast cellsdied.
Furthermore, a separate strain of mice with the samemutation as the first strain, but that had also been engineered toprevent IFNy production, were found to have almost as many mast cellsas normal mice, if not more. They concluded that the presence of highIFNy levels blocked mast cell development.
This research was supported by a grant from the National Institutes of Health.
Ryancollaborated with colleagues in the VCU Department of Biology, and theDepartment of Biochemistry at St. Jude Children’s Research Hospital inMemphis, Tenn.
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