But TNF-alpha failed to activate two nearby protein-coding genes on either side of Lethe. Reciprocally, stimuli that turned these two other genes on didn't affect Lethe. Meanwhile, two other pseudogenes that very closely resemble Lethe were not activated by TNF-alpha, as Lethe was.
Another surprising finding was that dexamethasone, a commonly prescribed anti-inflammatory steroid drug, activates Lethe. Various other steroid hormones that are not anti-inflammatory in nature, such as vitamin D or estrogen or a male steroid hormone, failed to boost Lethe levels.
"We're wondering whether there might be ways to artificially raise Lethe levels without steroids. These drugs have potentially deleterious side effects such as elevated blood pressure and blood sugar, thinning of bones and general suppression of the immune system," Chang said.
The study results suggest that not only Lethe but other pseudogenes undergo similarly selective awakenings to generate lncRNAs in response to different external inflammatory stimuli. "From the pattern of activated lncRNAs, you can tell what the cell has encountered a virus, a bacteria or something else," Chang said. "These patterns of activation may be able to serve as an indicator of what kind of inflammatory situation or pathogenic invasion is responsible."
A third surprise: While NF-kappa-B levels and activity within cells increase with an organism's advancing age, Lethe is dramatically downgraded with increasing age but eightfold more so in females. Lethe levels in spleens of older mice, compared with those of young mice, dropped 20-fold in males but 160-fold in females. "This gender-specific difference is not seen in young mice," Chang said. "Could this have any implications for the increasing female-to-male ratio, with advancing age, for autoimmune diseases in humans?"
|Contact: Bruce Goldman|
Stanford University Medical Center