In this infection model, high levels of GCN2 appear instead to nudge macrophages to make more pro-inflammatory mediators, resulting in rampant inflammation in the mice. In this environment, gene activity goes up to the point that the previously sluggish protein production is revived. "The overall affect is you get more inflammation," McGaha said.
And that's where potential new therapies for selectively blocking inflammation surfaced. When they knocked out GCN2, severe inflammation decreased and survival increased in animal models of septicemia. McGaha hopes the laboratory findings will eventually translate to hospital intensive care units.
"Macrophages can do a lot of things and only one of them is make inflammatory products, like cytokines, in response to infection," McGaha said. "They also are involved in wound healing and tissue reconstitution maitenance. So if a macrophage comes into an area that has a lot of mechanical damage, say from trauma, you don't want to make proinflammatory things because that will hurt the ability of the tissue to heal itself."
The good news is that drugs that block GCN2 already are under development to fight cancer and agonists exist that could bolster a positive immune response, such as increasing the potency of a vaccine, McGaha said. "If we can manipulate GCN2's activity in various contexts, we can help finetune the immune response in the direction we want."
Next steps including looking at how GCN2 manipulates immunity, particularly its impact on protein production.
MCG's Drs. Andrew Mellor and David Munn were the first to report that the fetus expresses IDO to help avoid rejection by the mother's immune system. Subsequent studies have shown tumors al
|Contact: Toni Baker|
Medical College of Georgia at Georgia Regents University