By David N. Leff
Ritual suicide seems to be a sporadic part of human tradition. Early Arctic explorers reported that Eskimos, when food was scarce, let their oldest family members leave the igloo to die peacefully of exposure on the ice. Until recent decades, Hindu culture required the widow of a deceased husband to join his corpse on the funeral pyre. In our own time, we recall the cult deaths by cyanide of 913 men, women and children in Jonestown, Guyana, in the 1970s, and the Heaven's Gate mass suicide of 18 men and 21 women in San Diego three years ago.
At the molecular level, the life of a cell features programmed suicide - apoptosis - as the normal way of removing damaged, worn-out or otherwise redundant cells from the body. Once apoptotic agents lay a cell low, the immune system's phagocytic (cell-eating) dumpster cells - macrophages - swarm to the scene and devour the debris. How do macrophages know where and when to report for this garbage-disposal duty?
Cell biologist Valerie Fadok, at the National Jewish Medical and Research Center, in Denver, proposes that, "what happens during apoptosis is that the dying cell's membrane gets scrambled and starts flipping a lot of lipids back and forth. One of the lipids that comes out is called phosphatidylserine - PS for short. We think that PS sits on the surface of the moribund cell, and is recognized by a macrophage. When a cell undergoes apoptosis. PS flips from inside that cell to the outside. So our newly discovered PS receptor can bind to the apoptotic cell. That sends a signal to the phagocyte that it needs to start engulfing. So it begins to pull this inert waste material inside itself and digest it.
"PS is an important constituent of the cell membrane," Fadok explained. "The important thing about it is that it appears to trigger the recognition signal. We had described in the early 90s that when macrophages eat apoptotic cells, they seem to recognize an alteration in the lipids on the surface of those cells. We had been searching for this receptor for the last 12 years, and finally were able to clone it."
Fadok is lead author of a paper in the current issue of Nature, dated May 4, 2000, titled "A receptor for phosphatydlserine-specific clearance of apoptotic cells." Its senior author is Peter Henson, who chairs the center's cell biology program.
Dying Cells Set Off Cytokine Shut-Down
"The major finding of this paper to us," Fadok told BioWorld Today, "is that this PS receptor is not only involved in engulfing apoptotic cells, but appears to mediate an anti-inflammatory pathway that we described a couple of years ago. That is, when macrophages see these dying cells, they are triggered to shut down inflammatory cytokine production.
"It's not just cytokines either," Fadok continued. "It's other molecules the cells produce to promote inflammation. We think this PS receptor could be a new kind of target for anti-inflammatory drugs. We know that if we take the antibody to this receptor and stimulate it, it would have the same effect as engulfing apoptotic cells."
To raise an antibody against PS, Fadok recounted, "the first thing we did was take cells we knew would recognize this lipid on the surface of apoptotic cells, and make antibodies against those cells. This was basically a shotgun approach - or a shot in the dark.
"So we came up with this anti-PS monoclonal antibody," she went on, "and it turned out to our surprise that this receptor was present not just on macrophages but on other cells that eat apoptotic cells - such as fibroblasts, endothelial and epithelial cells. So it's a very widespread receptor in the mammalian body."
Fadok foresees that "drug companies might be interested in making compounds that bind to this receptor. For inflamed lungs, skin, joints - just anywhere where inflammation is a chronic problem. Take asthma for example. You might want to make a compound that would actually stimulate our receptor; that would allow the body itself to shut down that inflammation."
To this scenario, Fadok adds a caveat: "We need to learn a lot more about this protein, where it is and what it does, before it would be a good drug target. But the fact that triggering this PS receptor actually decreases inflammatory cytokine production is a pretty interesting finding.
"Japanese scientists cloned the gene that encodes this receptor in 1998," she recalled, "from material in a human brain library. It resides on human chromosome 17.
"We found this gene in the GenBank database for comparing sequences," Fadok went on. "It apparently expressed a protein of unknown structure and function. But interestingly it had homologous sequences in C. elegans, the roundworm nematode, and in Drosophila, the fruit fly - where nobody knows what it does.
"So that's what got us interested in this human PS gene," Fadok explained. "We believe that it is a very old gene, conserved throughout evolution, specifically to help remove apoptotic cells, and - at least in mammals - trigger anti-inflammation."
But there's more to PS than just having macrophages get rid of the garbage left by cell suicide. Apoptosis is not the only way cells die. The other is necrosis - lysis - caused by irreversible damage, infection or injury.
'Strange Cytokine' Quells Immune Reaction
Fadok observed that "this receptor triggers release of the immune-system cytokine TGF beta - transforming growth factor beta. TGF-beta is a strange cytokine," she pointed out, "because it does a lot of different things. One thing it does is decrease cytokine production by macrophages. And it also suppresses the immune system in certain settings. One could envision a scenario where by dealing with programmed cell death - which is a good process in the body for clearing inflammation - the PS receptor would also have to prevent an immune response for something to which you don't really want to have an autoimmune reaction."
The National Jewish Medical Center has patents pending on the PS receptor antibody's hybridoma. "The only thing we're doing right now," Fadok said, "and that's still under negotiation, is licensing the hybridoma to a company that generates antibodies for a living. And then research laboratories will have access to our antibody."