title: Endogenous IL-1α is a chromatin-associated protein in mouse macrophages.
abstract: The cytokine interleukin-1α (IL-1α) is synthesized as a 31kDa peptide that lacks a leader peptide and is not secreted by the conventional secretory pathway. A distinctive characteristic of pro-IL-1α is the presence of a nuclear localization sequence in its amino-terminal moiety that allows its translocation to the nucleus. However no nuclear function(s) of the endogenous pro-IL-1α has been reported to date. In the present study, we used murine macrophages that produce IL-1α in response to pro-inflammatory stimuli, to gain further insight into the biology of the endogenous IL-1α protein in innate immune cells. We show that endogenous IL-1α is essentially found as a chromatin-associated nuclear protein in LPS-stimulated macrophages. In contrast to IL-1β, IL-1α was not released upon inflammasome activation unless significant cell damage occurred. IL-1β mRNA and protein levels were specifically decreased in IL-1α deficient macrophages after LPS stimulation. However, overexpression of human pro-IL-1α did not rescue this defective IL-1β production, suggesting that this finding might be related to the insertion of the targeting construct into the IL-1 locus, rather than to a specific nuclear function of pro-IL-1α. Finally, by using both genomic and proteomic approaches, we could not identify a nuclear function of IL-1α. Taken together, these observations suggest that in macrophages IL-1α primarily acts as an alarmin that is rapidly released upon cell damage to activate early mechanisms of host defense.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University Hospital of Geneva, 26 Avenue Beau-Séjour, 1211 Geneva 14, Switzerland. celinelammacchia@hotmail.com
authors.forename: Céline
authors.initials: C
authors.lastname: Lamacchia
authors.forename: Emiliana
authors.initials: E
authors.lastname: Rodriguez
authors.forename: Gaby
authors.initials: G
authors.lastname: Palmer
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus; D002843:Chromatin / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism*; D008070:Lipopolysaccharides; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D002843:Chromatin; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides