Recherche 2013


Lamacchia C, Rodriguez E, Palmer G, Gabay C.

Endogenous IL-1α is a chromatin-associated protein in mouse macrophages.

Cytokine. 2013 May 14. pii: S1043-4666(13)00175-0. doi: 10.1016/j.cyto.2013.04.010. [Epub ahead of print]
 
Source
Division of Rheumatology, Department of Internal Medicine, University Hospital of Geneva, 26 Avenue Beau-Séjour, 1211 Geneva 14, Switzerland; Department of Pathology-Immunology, University of Geneva School of Medicine, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Electronic address: celinelammacchia@hotmail.com.
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.
 
CONCLUSIONS:
The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in West/Central Africa. The genetic risk of developing RA conferred by a set of 28 Caucasian susceptibility SNPs is significantly different between the UK and Africa with p<0.001. Taken together, these observations strengthen the hypothesis that the genetic architecture of RA susceptibility is different in different ethnic backgrounds.