Skip to main content
  • Poster presentation
  • Published:

Novel intracellular function of IL-1 receptor antagonist type 1 in endothelial cells

IL-1 receptor antagonist (IL-1Ra) is a member of the IL-1 family that competitively inhibits the binding of IL-1 to its cell surface receptors, and thus acts as a natural IL-1 inhibitor. Four different IL-1Ra peptides are produced from the same gene by the use of alternative first exons, mRNA splicing, and alternative translation. One isoform is secreted (sIL-1Ra), while the three other isoforms remain intracellular (icIL-1Ra1, icIL-1Ra2, icIL-1Ra3). In a previous study, we observed that icIL-1Ra1 is produced in high amounts in the joints of mice with collagen-induced arthritis (CIA) and that the expression of icIL-1Ra1 coincided with the resolution of articular inflammation. Recently, we showed that mice transgenic for icIL-1Ra1 were protected from CIA in a similar manner to sIL-1Ra transgenic mice. However, as icIL-1Ra1 was also detected in the circulation, it was impossible to determine whether icIL-1Ra1 exerted its anti-inflammatory effect inside cells or through its interaction with cell surface receptors. To address this question, we examined the intracellular effects of icIL-1Ra1 on endothelial cell migration. IL-1a is produced as a 31 kDa protein (pre-IL-1a) that is cleaved to generate C-terminal mature IL-1a. The N-terminal region of pre-IL-1a contains a nuclear localization domain, and both pre-IL-1a and the 16kDa N-terminal IL-1a are able to migrate into the nuclei and to modulate endothelial cell migration. The migration of the endothelial cell line ECV was significantly increased in cells transfected with pre-IL-1a or N-terminal IL-1a propiece. In contrast, the addition of mature IL-1a in culture medium was devoid of any effect on cell migration, indicating that the effect of pre-IL-1a and 16kDa N-terminal IL-1a was independent of their interaction with cell surface receptors. Most interestingly, expression of icIL-1Ra1 in ECV cells completely reversed the effects of pre-IL-1a and N-terminal IL-1a. Immunofluorescence studies indicated that the N-terminal IL-1a was located in the nuclei. icIL-1Ra1 was located both in the cytoplasm and in the nuclei, and co-expression of icIL-1Ra1 modified the intracellular localization of the N-terminal IL-1a. In conclusion, this study demonstrates for the first time that icIL-1Ra1 may carry out important intracellular regulatory functions in endothelial cells.

Author information

Authors and Affiliations


Rights and permissions

Reprints and permissions

About this article

Cite this article

Gabay, C., Soussi, F. & Berti, M. Novel intracellular function of IL-1 receptor antagonist type 1 in endothelial cells. Arthritis Res Ther 5 (Suppl 3), 72 (2003).

Download citation

  • Published:

  • DOI: