By David N. Leff

Television commercials that act out human dramas pitting one painkilling drug against another are really touting the competing blessings of corticosteroidal and nonsteroidal analgesics. And when they assert that their headache or backache assuagement "contains the ingredient that doctors use most," they are of course alluding obliquely to aspirin.

Hippocrates, the father of medicine, said it first, some 25 centuries ago, when he prescribed a tea made from the bark of the willow tree. That infusion contained salicylic acid, aspirin's active ingredient.

How aspirin works to relieve pain and inflammation was a mystery until late in our own 20th century. Now we know that it blocks production of prostaglandins.

The dark ages of ignorance that for millennia hid aspirin's mechanism of action still prevail as to how those modern, TV-touted pills of guaranteed surcease get in their licks.

Molecular biologist Brian Seed, of Harvard University-affiliated Massachusetts General Hospital, in Boston, has threaded the maze of metabolic pathways by which the body's immune system copes with trauma, infection and other challenges — of which pain is a byproduct. His paper in Nature, dated Jan. 1, 1998, bears the title: "PPAR-g agonists inhibit production of monocyte inflammatory cytokines."

Among all the cytokines that the immune system's monocytes (the blood-borne form of macrophages in tissue) mobilize in the face of danger, the most proinflammatory is tumor necrosis factor (TNF). "Tumor necrosis factor," he told BioWorld Today, "is increasingly recognized as a central mediator of a variety of normal and pathological processes."

Seed also inculpates that over-eager, cell-signaling cytokine as "contributing to insulin resistance in adult-onset [Type II] diabetes mellitus." TNF does so, he explained, by antagonizing glucose uptake in that disease. He cites research by others as building "a pretty compelling case that TNF production by adipocytes [fat cells] may act in a feedback way to blunt their responsiveness to insulin."

Nowadays, Seed pointed out, "We think of TNF as a cytokine of acute infectious processes." As such, it gained its current name for an ability to lyse certain tumor cells in vivo. But originally, tumor necrosis factor was named cachectin, promoter of cachexia (bodily wasting), because of its "involvement in some central programming of energy metabolism by the body."

Looking at this glucose-suppressing role, Seed turned the metabolic tables on TNF by picturing a counter-regulatory pathway. He surmised that "things that regulate glucose consumption might, contrariwise, antagonize TNF production."

This speculative scenario led Seed and his co-authors to check into what a certain brand-new oral antidiabetic drug, thiazolidinedione by name, might be up to in the monocytes that trigger TNF release.

He observed that "the nuclear receptor that mediates differentiation of fibroblasts into fat cells is also present in monocytes. In other cells, a subcellular, membrane-bound organelle, the peroxisome, plays a starring role in the oxidation of fats. And a number of fatty acids proliferate peroxisomes in adipocytes.

Which is why that key receptor in the nucleus gets the acronym PPAR-g, standing for "peroxisome proliferator-activated receptor-gamma."

Japanese scientists discovered the anti-diabetic thiazolidinediones 15 years ago, Seed recalled. "But no one really understood their mechanism of action until a couple of years ago, when researchers at Glaxo Wellcome found that they were agonists of that nuclear receptor, PPAR-g."

He recalled that "agonists bind to receptors and do things, as opposed to antagonists, which bind receptors and block them. So it made a really neat connection: That oral anti-diabetic drug was actually acting as an agonist."

Seed continued in this vein: "Most of those are in the nuclear receptor family. All of the semi-synthetic steroids are in fact agonists.

"That," he continued, "was an unusual connection, in terms of our reasoning about monocytes. So it made sense for us to think about whether or not TNF production was inhibited by these drugs."

Whereupon, he and his co-authors put human blood monocytes in culture, then exposed them, together with the various agonistic compounds, to stresses that stimulate TNF production.

"As reported in our Nature paper," he recounted, "we found that these nonsteroidal compounds did indeed block TNF production."

Their second finding, he added, "was that some of these nonsteroidal, anti-inflammatory drugs are effective at doses way over the concentration needed to inhibit prostaglandins, which, like aspirin, is their known mechanism of action. And it turns out that some of these agents are also PPAR-g agonists. That is, they force adipocyte differentiation in fat cell lines."

Bonus Benefit Of Nonsteroidals

He explained: "What you find in rheumatoid arthritis, for example, is that you tend to get increasing clinical benefit with escalating dose, right up until you're limited by horrendous gastrointestinal side effects."

These results confirm Seed's belief "that part of the therapeutic benefit with this high-dose, nonsteroidal therapy may actually be due to suppression of inflammatory cytokines. This fits very nicely with a picture we have that says TNF and those other cytokines play a central role in the evolution of rheumatoid arthritis. And in fact, the thiazolidinediones might be reasonable candidates as anti-inflammatory agents."

Amgen Inc., of Thousand Oaks, Calif., has a research and development program in TNF binding proteins, Seed pointed out. "They supported our work," he said, "in using their expression-cloning methodology to identify targets of lead drug compounds. As a commercial partner with Massachusetts General Hospital," he added, "Amgen will have right of first refusal to any patentable research finding."

Seed's paper in Nature runs adjacent to complementary research reported by molecular biologist Christopher Glass and his co-authors at the University of California-San Diego. Its title: "The peroxisome proliferator-activated receptor-g is a negative regulator of macrophage activation." Its commercial sponsor is Glaxo Wellcome Research and Development, at Research Triangle Park, N. C. *

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