The Epistatic Interrelationships of IL-1, IL-1 Receptor Antagonist, and the Type I IL-1 Receptor

Abstract

Mice lacking the gene for the IL-1R antagonist (IL-1ra) show abnormal development and homeostasis as well as altered responses to infectious and inflammatory stimuli. A reduction in the level of IL-1 signaling, either by deletion of the receptor or increased expression of IL-1ra, does not affect development or homeostasis, but does alter immune responses. In this study we use genetic epistasis to investigate the interdependence of selected genes in the IL-1 family in the regulation of these developmental and immunological processes. Deletion of the gene encoding the type I IL-1R (IL-1RI) is epistatic to deletion of the IL-1ra gene. Therefore, all functions of IL-1ra depend upon the presence of a functional receptor; there is no other target. Similarly, overexpression of the mRNA encoding the secreted form of IL-1ra is epistatic to deletion of the receptor antagonist, leaving the role of the intracellular splice variants of IL-1ra unknown. The abnormal development of IL-1ra-deficient mice is probably due to chronic overstimulation of the proinflammatory pathway via IL-1, but a clear single pathological defect is not apparent. These results support the model that the only essential function of IL-1ra in both health and disease is competitive inhibition of the IL-1RI.

Decreased Fat Mass in Interleukin-1 Receptor Antagonist–Deficient Mice

“…2) Irikura et al (38) have characterized the inflammatory phenotype of IL-1Ra Ϫ/Ϫ mice and have crossed them with IL-1 receptor knock-out animals. These experiments have revealed that the low body weight of IL-1Ra-deficient mice can be rescued either by deleting the IL-1 receptor or by reintroducing a transgene coding for IL-1Ra.…”

Anti-inflammatory response is associated with mortality and severity of infection in sepsis

“…acute respiratory distress syndrome have been shown to have increased IL-1ra:IL-1␤ ratio in bronchoalveolar lavage fluid (28). It appears that the sole essential function of IL-1ra is the competitive inhibition of the IL-1RI (20). Previous studies have shown that from 50-to 500-fold excess of IL-1ra to IL-1␤ is necessary to inhibit IL-1␤'s action on effector cells in vitro (15).…”

Elastic-Vessel Arteritis in Interleukin-1 Receptor Antagonist–Deficient Mice Involves Effector Th1 Cells and Requires Interleukin-1 Receptor

“…Irikura et al 16 have shown that the induced phenotypic features and general malaise observed in C57BL/6 Il1rn Ϫ/Ϫ animals are suppressed by overexpression of IL-1ra or by elimination of IL-1R1. We show that a single functional copy of the IL-1R1 gene (Il1r1) is essential for the pathology of IL-1ra deficiency, which implicates IL-1 as the mediator of the disease process.…”