By David N. Leff

If the interplay of inflammation and autoimmune disease were a Greek tragedy, its cast of characters might line up something like this:

* Tumor necrosis factor (TNF) — a notorious proinflammatory cytokine that, when unleashed, brings on such diseases as rheumatoid arthritis and septic shock.

* Lipopolysaccharide (LPS) — a bacterial toxin that, when released in the bloodstream, instigates macrophages to produce TNF.

* Macrophages — white blood cells of the immune system, that secrete TNF in quantity to carry out injurious effects on LPS.

* Glucocorticoids — the steroid hormones that frustrate TNF production.

At the University of Texas Southwestern Medical Center in Dallas, a team of clinical researchers has unraveled a complex cellular pathway centered on TNF. They report their potentially therapeutic finding in the November 1997 issue of Molecular and Cellular Biology (a journal of the American Society of Microbiology) under the all-inclusive title: "JNK/Stress-activated protein kinase (SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: Glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK."

What this boils down to is their finding that glucocorticoid can inhibit expression of TNF by preventing LPS from activating an enzyme, stress-activated protein kinase (SAPK), which is required for TNF production by the macrophage.

The paper's senior author, rheumatologist Thomas Geppert, observed that "TNF has become a very interesting molecule because it plays such a central role in a variety of diseases, so anything affecting TNF production might potentially be a drug."

He added, "Current approaches to inhibit TNF production are expensive and require repeated injections, but if we could come up with a pill that blocks that production, it would be a real breakthrough."

Glucocorticoids fill a very broad shelf in the pharmacy of prescription and over-the-counter drugs — oral pills, systemic injections, topical ointments, aerosol inhalants. As immunosuppressants and anti-inflammatory compounds, they treat ailments from asthma, dermatitis and eye inflammation to colitis, muscular dystrophy, psoriasis, and rheumatoid arthritis. One familiar synthetic version is dexamethasone.

But these multipurpose mainstays of medical practice come with a kicker: Used for any length of time, they're toxic. Molecular biologist Jennifer Swantek, first author of the Dallas paper, pointed out: "Glucocorticoid side effects include osteoporosis, aseptic bone necrosis, cataracts, weight gain, heart disease, elevated blood pressure, diabetes, skin fragility and easy bruising."

Unknown: Virtual Panacea's Mode of Action

"For all their therapeutic utility in treating various diseases," Swantek told BioWorld Today, "and even though they've been used for years, nobody really knows the exact molecular mechanism for how glucocorticoids act." She and her co-authors set out to try filling this gap.

"Our first line of questioning," she recounted, "was to identify the cell-signaling pathways of various tyrosine kinases — the energy-transferring enzymes — that became activated in response to LPS stimulation of the macrophages to transcribe and translate the TNF gene.

"Then," she continued, "I shifted gears, knowing that glucocorticoids, including dexamethasone, were able to block production of various toxic cytokines, including TNF. So I reasoned: 'These kinases become activated by LPS. Glucocorticoids inhibit TNF production. Let's see if dexamethasone can block activation by LPS of any of these protein kinases. If so, that would implicate that particular enzyme in TNF regulation.'"

Working with mouse macrophages in culture, she and her co-authors identified that particular enzyme as one called SAPK — stress-activated protein kinase.

"We showed," Swantek said, "that not only was SAPK activated by LPS in the macrophage, but is required for production of TNF. And we found that dexamethasone was able to inhibit that LPS-induced activation of SAPK."

Pharmacological Potential? Definitely!

She summed up: "We may now have a potential mechanism as to how glucocorticoids actually act; how they are able to be anti-inflammatory, by inhibiting SAPK."

Asked if this new insight has any pharmacological potential, Swantek replied, "Definitely." Then she added: "If you could find a drug that blocks SAPK, then according to my research, that would inhibit TNF production. It would therefore be a great drug. It might not have those serious side effects associated with long-term glucocorticoid usage."

Her group is now working with a major pharmaceutical company, looking toward trials in laboratory animals, and eventual drug-discovery screening.

"I'm so excited about these findings," Swantek concluded, "and the potential benefits this research might lead to." *

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