The epistatic interrelationships of IL-1, IL-1 receptor antagonist, and the type I IL-1 receptor.
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.
Irikura
Vera M
VM
Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Lagraoui
Mouna
M
Hirsh
David
D
D000818:Animals; D000831:Animals, Newborn / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D004843:Epistasis, Genetic; D005260:Female; D006130:Growth Disorders / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology; D012795:Sialoglycoproteins / Q000172:deficiency / Q000235:genetics*; D016019:Survival Analysis
D016207:Cytokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins