Interleukin-1 and Interleukin-1 Antagonism

The polypeptide cytokine interleukin-1 (IL-1) affects nearly every tissue and organ system. IL-1 is the prototype of the pro-inflammatory cytokines in that it induces the expression of a variety of genes and the synthesis of several proteins that, in turn, induce acute and chronic inflammatory changes. IL-1 is also the prototypic “alarm' cytokine in that it brings about increases in a variety of defense mechanisms, particularly immunologic and hematologic responses. Most studies on the biology of IL-1 have been performed in animals, but human subjects have recently been injected with recombinant IL-1 and the results confirm the two fundamental properties of IL-1 as being both a mediator of disease as well as of host defense. However, in either situation, over or continued production of IL-1 leads to debilitation of normal host functions; therefore, reduction of IL-1 synthesis or its effects becomes a target of therapy in many diseases. In this review, the structure, gene expression, synthesis, and secretion of IL-1 are described. In addition, the two IL-1 surface receptors, possible signal transduction mechanisms, various biologic activities, and production of IL-1 during disease states are discussed. Similarities and differences between IL-1, tumor necrosis factor, and IL-6 are presented. Although various agents for reducing the synthesis and/or for antagonizing the effects of IL-1 have been proposed, the recent cloning of a naturally occurring IL-1 receptor antagonist (IL- 1ra) has opened new experimental and clinical approaches. The ability of this IL-1ra to block the triggering of IL-1 receptors in animals without agonist effects has reduced the severity of diseases such as hemodynamic shock, lethal sepsis, inflammatory bowel disease, experimental arthritis, and the spontaneous proliferation of human leukemic cells.