"Too much interleukin-1 can be extremely hazardous to yourhealth." That warning from John Sims, director of moleculargenetics at Immunex Corp. of Seattle, rings up the curtain onthe latest act in the drama of IL-1 and its enigmatic receptors.
You can't tell the heroes from the villains without a program(see sidebar).
The script for this extravaganza played out by immune-systemcells and cytokines is a paper in Friday's Science titled"Interleukin-1 Type II Receptor: A Decoy Target for IL-1 Thatis Regulated by IL-4." It sets the stage for IL-1's "reallydangerous" inflammatory onslaughts, and for prospective drugsto head it off at the pass in inflammatory and autoimmunediseases ranging from asthma to arthritis and psoriasis toleukemia to toxic shock.
Two protagonists share center stage: IL-1 receptors type I andtype II.
Type I, the Science paper explains, enables IL-1 to prolong thesurvival in vitro of major white blood cells, thepolymorphonuclear leukocytes (PMNs).
In normal health, PMNs (mainly neutrophils) commit cellularsuicide every few hours and are replaced. But in time of need,the immune system calls on IL-1, acting through its type-Ireceptor, to keep PMNs in business to repel non-specificinvaders. The neutrophils contain granules capable of killingbacteria or virus-infected cells and, said Sims, literally "spilltheir guts" to do so. They prevent the microbial flora withwhich the body cohabits from over-growing and overwhelmingtheir host.
To keep this symbiotic process from going overboard, enter IL-4. It antagonizes IL-1 activity by expressing its type-IIreceptor. As immunologist Alberto Montavani, a leading co-author of the Science paper, put it to BioWorld, "The mainfinding of the work we have reported is that IL-1's type-IIreceptor is essentially a decoy target, and of course the obviousimplication would be to use muteins of this binding molecule asdrugs, as anti-IL-1 biotechnological compounds." He added, "Infact, that decoy molecule is being used by the body as one of itsanti-IL-1 pathways."
Montavani heads the immunology laboratory of the MarioNegri Pharmacological Research Institute in Milan. This non-profit Italian foundation made headlines in early 1990 when itreleased results of the massive GISSI-2 heart-attack study,which it headed, comparing streptokinase with t-PA (tissueplasminogen activator).
Sims of Immunex is a co-author of the paper and collaboratorwith the Milan institute in exploring the intricate interplay ofthe IL-1 binding molecules. It was Sims who cloned andpatented both the I and II receptors.
Immunex, he told BioWorld, is initiating Phase II human trialsof its recombinant, soluble IL-1 type-I receptor, which alsosoaks up IL-1. Last month the company launched one suchclinical study, pitting the molecule against allergens that assailseasonal allergy sufferers. (Immunex estimates that 10 millionAmericans a year seek medical treatment for allergies andasthma.)
Earlier this year, trials began of type I's efficacy againstrheumatoid arthritis. In a few months, Immunex plans to addinflammatory bowel disease to its Phase-II roster.
In their collaborative, trans-Atlantic experiments, the scientistsfound that IL-4 does not itself cause PMNs to undergoapoptosis, but rather cuts off IL-1's life-prolonging effect onthese cells. Using monoclonal antibodies specific for receptors Iand II, they identified type II as the "molecular trap" releasedby IL-4-treated PMN cells to end IL-1's life-extending act.
This in vitro circumstantial evidence, Sims cautioned BioWorld,"is strong evidence that IL-1 type II receptor is a naturalantagonist of the cytokine, but not proof positive that it actualhappens in a living mammal." Ditto in SIRS, he said. "Patientswith systemic inflammatory response syndrome have elevatedcirculating serum levels of the decoy factor, which is a nicecorrelation, but not yet proof."
Sims pointed out that most symptoms of viral infection -- highfever, aches and pains, fatigue, loss of appetite -- are notcaused by the virus per se but by the IL-1 that rushes to thescene.
Researchers in both Seattle and Milan are turning now to drugdiscovery, seeking agents that can unleash the decoy factoragainst inflammatory diseases. "IL-1 receptor II appears tofunction as a physiological pathway in the regulation of IL-1activity in myelomonocytic cells that can be subverted bypathogens, and may provide a target for pharmacologicalintervention," Montavani said.
One promising candidate his group is studying isdexamethasone, a synthetic analog of hydrocortisone, "one ofthe most potent anti-inflammatory agents." But the Italians arealso exploring other cytokines that may release the moleculardecoy receptor, and in cells other than neutrophils.
Montavani sees the type-II receptor as "an alternative strategyfor inhibition of IL-1 in certain human malignancies, notablyacute myelogeous leukemia (AML), for which there is evidencethat IL-1 is an important cofactor." In AML, the malignant cellsspontaneously produce interleukin-1, which acts as a growthfactor to fuel these self-same cells. They respond withunbridled proliferation.
"Receptor type II would snatch away the IL-1 and break thefatal vicious circle," said Sims.
CAST OF CHARACTERS IN THE IL-1 RECEPTOR PLAY
-- Interleukin-1 (IL-1). A cytokine with many functions in theimmune system. Implicated heavily in the body's inflammatoryresponses. (The villain of this piece.)
-- Cytokines. Circulating proteins that bind to matchingreceptors on white blood cells. Important in cell-to-cellinteraction in the immune and inflammatory responses. Theyincludes monokines, produced by mononuclear phagocytes, andlymphokines, produced by lymphocytes.
-- Interleukin-1 receptors (IL-1R). Cell-membrane moleculesthat bind IL-1:
-- IL-1R-I. A transmembrane protein, the main form of IL-1 receptor, expressed in fibroblasts and T lymphocytes.
-- Receptor IL-1R-II. Expressed mainly in polymorphonuclearleukocyte (PMN) cells; inhibit IL-1 inflammatory activity bybinding that cytokine, and keeping it from reaching its type-Ireceptor. (The hero)
-- PMN (polymorphonuclear leukocyte). Myeloid whiteblood cells, mainly neutrophils, with limited lifespan. IL-1strongly promotes PMN's survival by staving off itsprogrammed cell suicide. (So do gamma interferon,granulocyte-macrophage colony-stimulating factor and tumornecrosis factor.)
-- Interleukin-4. A cytokine that neutralizes IL-1, thuscounteracting its life-extending act in PMNs.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.