Interleukin-1 in disease.

As outlined in this review, the inflammatory cytokine interleukin-1 (IL-1) mediates a number of pathological processes associated with disease. To prove a role for IL-1, a variety of modalities have been used to block the production and/or activity of IL-1. These include agents which inhibit or reduce 1) IL-1 transcription and/or synthesis, 2) the processing of pro-IL-1 beta into its mature forms, 3) the secretion of IL-1 beta, 4) the activity of IL-1 using neutralizing anti-IL-1 antibodies or 5) soluble (extracellular) IL-1 receptors, 6) the ability of IL-1 to bind to its receptors using receptor blockade, 7) the availability of surface receptors using agents which down-regulate receptor expression or (8) agents which affect IL-1-mediated signal transduction. Some of these modalities have already entered clinical trials. Clearly, the therapeutic advantage of reducing the activity of IL-1 resides in preventing its deleterious biological effects without interfering with host defense and homeostasis. For example, blocking IL-1-induced prostaglandins is one target in treating inflammatory diseases. Drugs inhibiting cyclooxygenase have well-known toxicities because they block the normal physiologic synthesis of prostaglandins in many tissues such as platelets and gastric lining cells. Blocking IL-1, in contrast, reduces only that portion of prostaglandin synthesis due to elevated IL-1, sparing the synthesis of prostaglandins necessary for physiologic homeostasis. A similar case can be made for endogenous nitric oxide. Thus, there is a unique pharmacological advantage to blocking IL-1 in disease.