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Document Page 396 synthetic agents with the ability to modulate IL-1 responses. Here we review the present knowledge of the IL-1 system and the attempts toward the development of its modulators. A. Cytokines and Physiological Responses Cytokines are multifunctional hormones produced by a variety of cells to carry out a wide range of overlapping biological actions including communication within the immune system and between other cell types. They are produced by macrophages, endothelial cells, fibroblasts, keratinocytes, T cells, B cells, and natural killer cells in response to injury and infection [7]. Upon production they act either locally or as systemic intercellular signaling factors and induce the production of other cytokines for continuing their communications via cell surface receptors. The cytokines network also has associated with it a complementary set of soluble or membrane-bound antagonist or mediator molecules that are capable of shutting down these effects [8]. During infection and injury, the leukocytes adhere themselves to the endothelium and migrate into tissues. Cells like T-lymphocytes, monocytes, macrophages, and neutrophils collect themselves as inflammatory infiltrate. Once within the tissues, these cells neutralize the microorganisms or infected cells, secreting other cytokines that can modulate the adhesion molecule expression on the endothelium. In addition, chemotactic signals are delivered to cells passing in the circulation. Cytokines are also involved in tissue repair, i.e., remodeling of connective tissues and revascularization of damaged areas. Soluble mediators are released from the site of damage into the circulation to act in an endocrine fashion. The cytokines then control hepatic responses to tissue damage. During the regulation of hematopoiesis, cytokines induce the production and release of a number of colony-stimulating factors and other interleukins. Thus induced factors are responsible for the replacement of leukocytes and erythrocytes that were lost after trauma. A large number of cytokine molecules have been characterized [7]. Structurally it appears that these cytokines can be classified into the following main groups based on their folding pattern: 4-helix bundles, beta-trefoil, beta sandwich, EGF-like, beta cysteine knot, and alpha/beta. Thus far the structures of many representatives of each family have been solved by both x-ray crystallography and NMR (Table 1). Extensive experimentation has indicated that despite a large degree of structural diversity, there is a large degeneracy in the cytokine network and the molecules have a wide range of overlapping biological functions. For example, IL-1, TNF, PDGF, and TGFB all exhibit similar biological behavior. The structures of the receptors for these molecules have not been forthcoming and only three examples of the extracellular domains of the receptors have been reported. They are growth hormone receptor in complex http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_396.html [4/5/2004 5:44:02 PM]
Document Table 1 Known Three-Dimensional Structures of Cytokines Brookhaven Structure Molecule Type Code Determined by Interleukin-1 alpha (IL-1α) Beta trefoil 2ILA X-ray crystallography Interleukin-1 beta (IL-1β) Beta trefoil 1ILB, 2ILB, 4ILB, 5ILB, 6ILB Interleukin-1 receptor antagonist (IL-1ra) Fibroblast growth factor (acidic) (aFGF) Fibroblast growth factor (basic) (bFGF) Granulocyte-colony stimulating factor (G-CSF) X-ray crystallography and NMR Beta trefoil 1ILR, 1IRP X-ray crystallography and NMR Beta trefoil 1AFC X-ray crystallography Beta trefoil 1BFG X-ray crystallography Long-Chain 4 helix bundle Growth hormone Long-Chain 4 helix bundle Leukemia inhibitory factor (LIF) Long-Chain 4 helix bundle Granulocyte-macrophage colony stimulating factor (GM-CSF) Short-Chain 4 helix bundle Interleukin-2 (IL-2) Short-Chain 4 helix bundle Interleukin 4 (IL-4) Short-Chain 4 helix bundle 1RHG, 1GNC X-ray crystallography 1HGU X-ray crystallography 1LKI X-ray crystallography 1CSG, 1GMF X-ray crystallography 3INK X-ray crystallography 1BBN, 1ITM, 2CYK NMR Interferon gamma (IFN-γ) Dimeric 4 helix bundle 1IKI X-ray crystallography Interleukin 10 (IL-10) Dimeric 4 helix bundle 1ILK X-ray crystallography Nerve growth factor (NGF) Beta cysteine knot 1BET, 1BTG X-ray crystallography Platelet derived growth factor (PDGF) Beta cysteine knot 1PDG X-ray crystallography http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_397.html (1 of 2) [4/5/2004 5:44:05 PM] Page 397
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