From the itch of poison ivy to the agony of rheumatoidarthritis, the main standbys of doctors and their patientsare the glucocorticosteroids. For decades, physicians havebeen prescribing these potent inhibitors of immuneresponses and inflammation to relieve the chronicsymptoms of lupus, psoriasis and asthma, to name just afew, and the milder discomforts of pink eye, insect bitesand eczema.
In fact, a standard guide to prescription drugs lists 54diseases treatable by hydrocortisone, the natural form ofglucocorticosteroids. They cover virtually every field ofmedicine, from endocrine, rheumatic and collagendisorders to skin, eye and allergic diseases, among others.
Yet this same reference work (1994 edition) advisesphysicians that "No generally accepted explanation of thesteroids' [anti-inflammatory and autoimmune] propertieshas been advanced."
If the current issue of Science, dated Oct. 13, 1995, isanything to go on, future editions will be able, at longlast, to specify the molecular mechanisms that makesteroids work.
Two back-to-back papers in Science unveil the roleplayed by steroids in combating a nefarious moleculenamed "nuclear factor kappa-B," but much better knownby its acronym, NFkB.
"A lot of pharmaceutical and biotechnology companiesare trying to block NFkB," observes molecular biologistAlbert Baldwin Jr., who teaches at the University ofNorth Carolina's Lineberger Comprehensive CancerCenter in Chapel Hill. He and his associates, Baldwintold BioWorld Today, "were the original cloners, in 1991,of IkBa," a gene that inhibits the NFkB gene.
Baldwin is senior author of the Science paper titled "Roleof transcriptional activation of IkBa in mediation ofimmunosuppression by glucocorticoids."
"What we found," he explained, "is that I-kappa-B-alpha,which inhibits the transcription factor NFkB, is itselftranscriptionally up-regulated by glucocorticoids. Therationale here," he continued, "is that NFkB regulatesmany genes involved in the immune system response,such as cytokines and cell-adhesion molecules. Theseattract lymphocytes and macrophages to the site ofinflammation.
"The important point," Baldwin pointed out, "is thatNFkB regulates all of these immune and inflammationgenes. The mechanism of their induction is the movementof that NFkB transcription factor from the cell'scytoplasm into its nucleus, in response to aninflammatory cytokine, such as tumor necrosis factor orinterleukin-1."
He continued: "So by up-regulating the inhibitor ofNFkB, namely IkBa, we have found a general mechanismfor blocking NFkB activation, which then down the lineblocks the activation of all these inflammation andimmune response genes."
Baldwin cited two biotech firms as leaders in the anti-NFkB movement, Signal Pharmaceuticals Inc., SanDiego, and Tularik Inc., South San Francisco. He himselfis working with one of them in endeavoring to "designsome more rational inhibitors of the NFkB pathway," _but prefers not to identify which.
Molecular pharmacologist Michael Karin, senior authorof the second Science paper, is a scientific co-founder ofSignal. (See BioWorld Today, Feb. 9, 1994, p. 1.) Hisarticle bears the title, "Immunosuppression byglucocorticoids: inhibition of NFkB activity throughinduction of IkBa synthesis."
Baldwin said that he and Karin "are the best of scientificfriends. We share a lot of data freely with each other.Karin's approach involves more animal work," heobserved, "which is absolutely important. Ours is morecell culture."
Immunopharmacologist David Anderson is Signal's vice-president of drug discovery and preclinical development.He told BioWorld Today: "A lot of Michael Karin's workis feeding into our company from the standpoint that welicensed the technology for enzymes that modulatetranscription activation. He's one of our scientificadvisers, so we're working with him on drugs thatmodulate NFkB.
"This new finding, both by Karin and Baldwin,"Anderson said, "shows us ways that they are affectingother genes through non-classical means of transcriptionactivation. They don't bind directly to DNA. They bind toother regulators of transcription, and those are theapproaches that we've targeted to block the transcriptionactivation process."
He added, "We have some novel non-corticosteroidaldrugs that modulate this transcription factor, for whichwe're now in the process of defining efficacy and safetyin animal studies. The desired outcome being the anti-inflammatory or immuno-suppressant effects, and less ofthe toxicity of the glucocorticoids, because of theirmetabolic effects."
Signal has filed patent applications on these newcompounds, Anderson said. "They modulate theintracellular signaling process, which activates thetranscription factors. They're more novel than theglucocorticoids, which bind to their receptors andmodulate genes," he observed. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.