Sci. Aging Knowl. Environ., 8 October 2003
Taking a Tumble
Lung protein flips to stimulate, rather than block, inflammation
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/40/nw138
Key Words: cytokines connectins calreticulin CD91 macrophages
A protein's gymnastics suggest one way the body defends itself from dangerous microbes without fomenting destructive inflammation. According to a new study, the lung molecule somersaults on immune cells to stimulate inflammation instead of blocking it. The work might explain the molecule's seemingly contradictory effects.
Cells of the immune system malfunction in some diseases and with increasing age, leading scientists to wonder how the body controls them (see "Immunity Challenge"). For example, the lungs face a constant barrage of microbes, and the elderly are particularly susceptible to infections such as pneumonia. Some work suggests that surfactant proteins A and D (SP-A and SP-D) in the lung grab foreign molecules, then attach to immune cells and goad them into action. But other results contradict that idea. Removing SP-A or SP-D from mice augments--rather than dampens--the immune response. Immunologist Peter Henson and colleagues at the National Jewish Medical and Research Center in Denver, Colorado, wondered whether the proteins might send both anti- and pro-inflammatory signals.
To investigate, the team treated lung immune cells with SP-A, SP-D, or nothing before dousing them with an inflammation-inducing bacterial protein. The surfactant proteins reduced the cells' production of immunity-prodding molecules compared with the control treatment. Further experiments revealed that SP-A and SP-D bind to a cell surface protein called SIRP and block activation of p38, a protein that ignites inflammatory signals.
Surfactant proteins consist of a "head" and a "tail." The head binds to foreign bodies or to remnants of damaged host cells, and the tail sticks to intact immune cells. Henson and colleagues wanted to find out which portion quashes inflammation. Adding only the head region of SP-A to immune cells blocked p38 activation and production of inflammatory molecules. Tails alone, on the other hand, stimulated p38 and inflammation. The researchers propose that in the absence of infection, surfactant protein heads bind to SIRP to shut down inappropriate inflammation--which would explain why mice without the molecules overreact to infection, says Henson. When invaders abound, the head gloms onto the trespassers, and the tail binds to immune cells to spur inflammation. Initial tests supported this idea. The researchers combined cell debris--which stands in for the bacterial molecule by mimicking the destruction that occurs during infection--with SP-A. Adding the mixture to immune cells spurred inflammation, but SP-A alone quelled it.
The paper "adds a lot to the field," says infectious-disease researcher Kevin Harrod of the Lovelace Respiratory Research Institute in Albuquerque, New Mexico. The results suggest that whether the proteins stimulate or inhibit inflammation "depends on how SP-A and SP-D are oriented when they bind to a receptor," he says. Pulmonary biologist Thomas Korfhagen of Cincinnati Children's Hospital Medical Center in Ohio notes that surfactant proteins cohabit with lipids, which can dampen immunity. He'd like to see studies confirm that the proteins rather than the lipids prevent inflammation. Surfactant proteins falter in certain diseases, such as cystic fibrosis; Henson wonders if the proteins also flag with age. If so, researchers might be able to train the molecules to do new tricks to maintain immunity.
--R. John Davenport
October 8, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150