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IMMUNOLOGY Inflammatory Villain Turns Do-Gooder Prostaglandin Findings Suggest New Approach to Taming Inflammation A team of Harvard Medical School scientists has recently discovered an unexpected twist in one of the more puzzling of physiological scenarios—the disappearance of immune cells from a previously active site of inflammation. "The big take-home message here is that the initial injury is related to the resolution of inflammation," said Charles Serhan (above, front). His colleagues are (l to r) Bruce Levy, Karsten Gronert, and Clary Clish. Below, the quelling of inflammation is the result of a specific sequence of events set in motion at the beginning of an inflammatory attack. To investigate the sequence, Serhan and his colleagues created inflammation in a small air pouch on the back of a mouse. They found that as neutrophils rush to the site of inflammation (top), they produce leukotriene B4 (LTB4), which recruits more cells into the pouch. Neutrophils also produce cyclooxygenase-2 (COX-2), which leads (middle) to the production of prostaglandin E2 (PGE2). PGE2 causes a switch from a pro-inflammatory to an anti-inflammatory strategy: 15-lipoxygenase (15-LO) is induced, leading to lipoxin A4 (LXA4) production (bottom). Illustration by Jeff Cleary. Photo by Graham Ramsay This final, or resolution, phase of inflammation has traditionally been depicted as a passive, almost anticlimactic event—a petering out of immune activity. But Charles Serhan, Bruce Levy, and their colleagues have found that resolution is the culmination of a specific sequence of molecular events that is set in motion at the beginning of an inflammatory attack—and carried out by a surprising set of molecular players. The findings, which appear in the July Nature Immunology, could lead to a new strategy for quelling inflammation. Many drugs try to tame inflammation by inhibiting molecular events occurring at the beginning of the immune response. However, rather than nip an inflammation in the bud—which may thwart the body's own attempt to heal—a better approach may be to enhance the activity of these natural resolution-promoting compounds. "They're good-guy signals, and we may want to enhance them," said Serhan, HMS professor of anesthesia at Brigham and Women's Hosptial. To piece together the story, the researchers launched an inflammation in a small air pouch on the back of a mouse and sampled the volatile brew inside at timed intervals all the way to resolution. Until now, nobody had actually monitored the events leading up to resolution. The researchers discovered that as immune cells rushed into the sac, they produced two compounds known to incite inflammation, leukotriene B4 (LTB4), followed by prostaglandin E2 (PGE2). The cells then switched over and began producing an anti-inflammatory compound, lipoxin A4 (LXA4). Soon after, the flow of new immune cells dropped and inflammation eventually resolved. To see whether the PGE2 middleman might be causing the switch to LXA4, the researchers mixed it with the LTB4-producing immune cells. Sure enough, the cells began producing an enzyme required for lipoxin. Deprived of prostaglandin, the cells could not produce the enzyme. "Prostaglandin is turning on the machinery needed to make the enzymes that make lipoxins," Serhan said. Biological Role Reversal The discovery that PGE2, thought to incite inflammation, is actually doing the opposite—setting the stage for resolution—is but one of several plot twists offered by this new scenario. To make the prostaglandin, cells must first produce cyclooxygenase-2 (COX-2)—the very molecule that many anti-inflammatory drugs inhibit. "Our current thinking is that by inhibiting prostaglandin formation by using COX-2 selective inhibitors, you may be delaying the natural resolution of inflammation," Serhan said. "Instead, the way to approach anti-inflammation may be to use mechanisms that expedite resolution. One way to do this is to hasten the formation of LXA4." Another is to create analogs of LXA4 that are longer lasting and more powerful. Serhan and Levy are currently working to create such molecules. "A true anti-inflammatory agent would be something that would promote resolution," said Levy, HMS assistant professor of medicine at Beth Israel Deaconess Medical Center. Although prostaglandin E2 steals the limelight in the latest study, the lipoxins have been Serhan's main focus for more than a decade. In that time, he and his colleagues have discovered that lipoxins not only stop immune cells such as neutrophils from entering an area of inflammation but also signal monocytes and macrophages to clean up afterwards. The Peace Maker To confirm that LXA4, which is produced by neutrophils themselves, actually does play a role in resolution, they examined the chest cavity fluids of patients with and without inflammatory disease. Only those with inflammatory disease displayed LXA4 activity. To get a better sense of how and when the neutrophils were producing lipoxin and the other inflammatory agents, the researchers monitored the rise and fall of each in the pouched mice. Strikingly, the consecutive production of LTB4, PGE2, and LXA4 corresponded to the waxing and waning of immune cells. Further experiments confirmed that LTB4 and LXA4 were responsible, on the one hand, for inciting inflammation and, on the other, for dampening it. Even more impressive—and unexpected—was the way the cells make the switch between the two tactics by turning on prostaglandin production. The researchers found that PGE2 works by inducing the enzyme required for lipoxin production. Intriguingly, this enzyme, 15-lipoxygenase (15-LO), is found naturally in the neutrophils of people with chronic inflammatory disease. "That's a function that's not present in circulating neutrophils from healthy donors," said Levy. The details of the story remain sketchy, but a message is emerging. "There's something that's happening in chronic inflammation that's enabling the host to generate 15-LO, and if we use COX-2 inhibitors, that may affect the leukocytes' capacity for 15-LO formation," said Levy. "It may interrupt the ability of the host to naturally resolve." Serhan concurs. "If you're thinking about therapeutic approaches, you probably want to spare COX-2 and use agonists of resolution," he said. "We really need to be focusing our attention on resolution." —Misia Landau