A bee sting raises an angry red welt on the skin at the site of the ouch.As a rule, this painful inflammation subsides in a few days.
But the immune defenses of some people break that rule, and thesting becomes suddenly lethal. What kills the person, sometimes inseconds, is anaphylactic shock _ an explosion of inflammatoryweapons in the immunity arsenal.
What triggers this acute overkill reaction is a misfiring of immunememory. Certain antibodies, called immunoglobulin E (IgE), whenconfronted with the bee venom, "remember" that they've encounteredthat self-same antigen before, and launch an all-out, out-of-proportion, counter attack.
Among the many kinds of anti-personnel molecules in this immuneonslaught are histamines (the scourge of allergies and asthma), and acluster of cellular bomblets called leukotrienes (LTs), name-taggedA, B, C, D, E and so on. These are rated 100 to 1,000 times morepotent than histamines at mounting a take-no-prisoners inflammatoryraid.
One leukotriene, LTB4 is a fatty acid, generally thought byimmunologists and molecular biologists to be a chemoattractant,recruiting leukocytes to fight off invading antigens. Now thesescientists may have another thing coming, thanks to a paper intoday's Nature. Its title: "The PPARa-leukotriene B4 pathway toinflammation control."
That pathway, it turns out, also leads to obesity control.
PPARs _ peroxisome proliferator-activated receptors _ are gene-transcription factors. (Peroxisomes are arrays of enzymes that breakdown fatty acids.) Leukotriene B4, a mediator of inflammation, itselfa fatty acid, activates PPARa And PPARa regulates fat metabolism.
"What makes that convoluted metabolic discovery in Natureexciting," biochemist Charles Serhan told BioWorld Today, "is that itopens up a conduit for testing new theories about inflammation, andhow this receptor/ligand interaction also regulates fat metabolism."
Serhan wrote a "News & Views" editorial accompanying the Naturearticle. That paper's first author is molecular biologist PallaviDevchand, a post-doctoral fellow in the Institute of Animal Biologyat the University of Lausanne, Switzerland.
"What we have done," Devchand told BioWorld Today, "is identify acommon mechanism by which you can degrade fatty acids in thebody. In our paper we showed that an inflammatory fatty acid such asLTB4 is degraded by the same pathway that is used by ahypolipidemic drug _ a drug that decreases triglyceride levels inyour body."
Double-Duty Designer Drugs
"This means," she continued, "that you can target that molecule andactivate it in order to degrade fatty acids in general. So for somethinglike obesity, where you want to metabolize fat fast, or in cases likeatherosclerosis, where you want to get rid of fat build-up, you'd beable to model drugs that target this PPARa receptor."
Devchand pointed out that "LTB4 is itself a fatty acid derivative, asare many inflammatory signals in the cell. So we're looking at onemolecule that you could target for either an anti-inflammatory effect_ against conditions such as rheumatoid arthritis, lupus and psoriasis_ or a fat-lowering effect _ against obesity, hyperlipidemia andcardiovascular disease.
"It's only now that we know that the same molecule can be used totarget these two different kinds of disorders," she observed. "Untilnow we didn't really know how the drugs that are on the market forlowering serum cholesterol and lipids, for example clofibrate[Atromid], actually work.
Besides elucidating their function, she added, "We can now go in andmake drugs that are better in terms of fitting the molecule better, orwe can actually design a specific new drug for the receptor."
Or as Serhan told BioWorld Today: "This new PPARa target, playinga role as a switch between inflammation and fat metabolism, nowopens up the window to test drugs in both directions. Drugs known tolower lipid levels can now be tested as to how they regulateinflammatory events that occur in minutes or hours.
"And vice versa," he went on, "existing drugs that may not be in theclinic yet, but impact on inflammation, may have a longer impact ifwe test them out in fat regulation, which takes days and weeks at atime."
Pallavi put that time-factor point into this perspective: "A hypolipiddrug is a foreign molecule to the body, so it's actually antigenic, apoison in some ways. So you want that molecule, which you use toactivate this receptor, to be degraded eventually. You don't want ithanging around too long."
When Does Bee-Sting Welt Go Away?
In other words, she went on, "How does the ligand/receptor systemknow when to turn off the inflammation? How long does its cellularinformation have to hang around?"
She and her co-workers put this question to a mouse used for testinginflammatory agents. The model is known to researchers as MEST _the "mouse ear-swelling test." It consists of daubing a chemicalirritant on the sensitive ears of the animals, and measuring how longit takes the swelling to subside.
The group generated knockout mice lacking the gene for the PPARareceptor, and compared them with wild-type receptor-plus animals.Both cohorts had its ears rubbed with arachidonic acid _ theprecursor molecule that produces leukotrienes.
"In a mouse that has no receptor," Devchand recalled, "theinflammation due to LTB4 is prolonged. In a wild-type animal thathas the receptor, you're looking at inflammation going away in, say,half an hour. In the knockout, it would stay on for three or four hours,but eventually its swelling too goes away."
This delayed subsidence, she pointed out, "tells us that even thoughthere's one pathway that the body uses to control the inflammationinformation, there are redundant pathways that get rid ofleukotrienes. So it's not the only pathway _ which is a reassuringthing." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.