The JCI paper suggests that the same JAK/STAT pathway plays a key role in asthma by operating even in the absence of viral infection.
First, the researchers located Stat1 in epithelial cells they had brushed from people's airways and in biopsy samples of the airway lining. In healthy subjects and subjects with chronic bronchitis, Stat1 was usually in the cytoplasm, where it presumably was inactive. But in samples from 24 people with asthma, it was usually in the nucleus, presumably switching on genes.
Stat1 enters the nucleus after one of the JAK proteins gives it a phosphate group. The researchers found phosphorylated Stat1 in epithelial cells brushed from the asthmatic subjects. But the protein was not phosphorylated in immune cells retrieved from the airway or in either cell type from the nonasthmatic subjects. Other proteins that switch on inflammation-triggering genes were not phosphorylated in any of the samples.
The researchers then looked for consequences of Stat1 activation, focusing on the products of genes Stat1 is known to turn on. They found abnormally high levels of three inflammatory proteins in cells brushed from the airway. These were Stat1 itself, ICAM-1, which makes immune cells stick to the airway, and a protein that regulates interferon production. Levels of ICAM-1 correlated with the number of immune cells (mostly T cells) in the biopsy samples.
Finally, the researchers looked for the cause of Stat1 activation.
Interestingly, interferon-gamma, a critical anti-viral mediator and the normal trigger for epithelial Stat1 activation, was present only at the usual low level found in subjects with asthma.
"These findings, along with others we've made in the past several years,
strongly suggest that this epithelial signaling pathway is unnecessarily
activated in people with asthma," Holtzman says. "In contrast to what has been
presented in the past, asthma appears
Contact: Linda Sage
Washington University School of Medicine