The research project will determine the in vivo role of interleukin-1 receptor antagonist (IL-1ra) which is a naturally-occurring polypeptide that bears 26% homology to IL-1Beta. By occupying the Interleukin-1 (IL- 1) receptor site, but failing to initiate the cellular response to IL-1, IL-1ra may serve as an inhibitor of IL-1-mediated inflammatory processes. Il-1ra has been shown to inhibit inflammatory responses when the recombinant protein was administered to animals. In order to test whether IL-1ra is an endogenous modulator of IL-1-related inflammatory processes in vivo, mice will be genetically manipulated either to be lacking the IL-1ra gene ('knockouts""""""""), or having supernumerary copies of it (""""""""transgenics""""""""). This will provide a tool in which the effect of endogenous IL-1ra have been totally eliminated, or in which extra copies may confer an additive effect of the gene product. Knockout and transgenic mice will then be characterized in term of embryonic and fetal development and tendency to the spontaneous occurrence of inflammatory disorders. Susceptibility to inflammation will be tested by creating three experimental models of inflammation and characterizing them in transgenic and knockout mice: endotoxin-induced shock, monoarticular (rheumatoid) arthritis and endometriosis.
| Devlin, Cecilia M; Kuriakose, George; Hirsch, Emmet et al. (2002) Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci U S A 99:6280-5 |
| Mussalli, G M; Blanchard, R; Brunnert, S R et al. (1999) Inflammatory cytokines in a murine model of infection-induced preterm labor: cause or effect? J Soc Gynecol Investig 6:188-95 |
| Irikura, V M; Hirsch, E; Hirsh, D (1999) Effects of interleukin-1 receptor antagonist overexpression on infection by Listeria monocytogenes. Infect Immun 67:1901-9 |
| Hirsch, E; Blanchard, R; Mehta, S P (1999) Differential fetal and maternal contributions to the cytokine milieu in a murine model of infection-induced preterm birth. Am J Obstet Gynecol 180:429-34 |
| Hirsch, E; Irikura, V M; Paul, S M et al. (1996) Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci U S A 93:11008-13 |
