INTERLEUKIN-1 RECEPTOR ANTAGONIST IS A MEMBER OF THE INTERLEUKIN-1 GENE FAMILY - EVOLUTION OF A CYTOKINE CONTROL MECHANISM

Interleukin 1 receptor antagonist (IL-1ra) is a protein that binds to the IL-1 receptor and blocks the binding of both IL-1-alpha and -beta without inducing a signal of its own. Human IL-1ra has some sequence identity to human IL-1-beta, but the evolutionary relationship between these proteins has been unclear. We show that the genes for human, mouse, and rat IL-1ra are similar to the genes for IL-1-alpha and IL-1-beta in intron-exon organization, indicating that gene duplication events were important in the creation of this gene family. Furthermore, an analysis of sequence comparisons and mutation rates for IL-1-alpha, IL-1-beta, and IL-1ra suggests that the duplication giving rise to the IL-1ra gene was an early event in the evolution of the gene family. Comparisons between the mature sequences for IL-1ra, IL-1-alpha, and IL-1-beta suggest that IL-1ra has a beta-stranded structure like to IL-1-alpha and IL-1-beta, consistent with the three proteins being related. The N-terminal sequences of IL-1ra appear to be derived from a region of the genome different than those of IL-1-alpha and IL-1-beta, thus explaining their different modes of biosynthesis and suggesting an explanation for their different biological activities.