The IL1 receptor antagonist is a protein that binds to IL1 receptors and inhibits the binding of IL1-alpha and IL1-beta to their receptors. As a result, the biologic activity of these two cytokines is neutralized in physiologic and pathophysiologic immune and inflammatory responses. Two forms of IL-1 RA have been described: intracellular (icIL-1RA) and secretory (sIL-1RA) (Lennard, 1995).
Using a panel of somatic rodent/human cell hybrids, Steinkasserer et al. (1992) showed that the IL1RA gene maps to 2q. Using a length variation polymorphism located within the second intron of the IL1RA gene, together with a polymorphism of the IL1a gene, they mapped the IL1RA gene to 2q14-q21 in the same region as IL1a and IL1b. The findings suggest that an early gene duplication event resulted in the creation of an interleukin-1 gene family. By fluorescence in situ hybridization, Lennard et al. (1992) mapped the gene to 2q13-q14.1. The two forms of interleukin-1 receptor also map to the same area of chromosome 2.
The protein encoded by this gene is a member of the interleukin 1 cytokine family. This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses. This gene and five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures and gastric cancer. Four alternatively spliced transcript variants encoding distinct isoforms have been reported.
IL1RA is a naturally occurring cytokine or hormone-like molecule that functions as a specific receptor antagonist. Carter et al. (1990) cloned the gene for interleukin-1 receptor antagonist protein and studied the expression of the gene as well as the biologic characteristics of the protein, which they referred to as interleukin-1-receptor antagonist protein (IRAP). They found that it specifically inhibited IL1 bioactivity on T cells and endothelial cells in vitro and was a potent inhibitor of IL1 induced corticosterone production in vivo. Arend (1991) reviewed the properties of the IL1 receptor antagonist.
Hurwitz et al. (1992) studied the role of IL1 in the ovary, using a solution hybridization/RNase protection assay to test for expression of the IL1 gene, its type I receptor (IL1R) and its receptor antagonist (IL1RA). Their findings revealed the existence of a complete, highly compartmentalized, hormone-dependent intraovarian IL1 system. IL-1 plays important roles in follicle development, steroidogenesis, ovulation, and luteal function (Terranova et al, 1997). Also, Hogquist et al. (1991) demonstrated that both interleukin-1 a and b are involved in apoptosis (cell death). IL-1RA is most likely involved in these processes as well.
Expression regulated by
FSH, LH, Growth Factors/ cytokines, IL-1b, IL-8
Kol et al. (1999) found that Il-1b has a stimulatory effect on IL-1RA expression in rats. It was also found that IL-1RA expression peaks at the time of ovulation, suggesting a role for FSH and LH in IL-1RA expression.
Ujioka et al. (1998) studied the regulation and involvement of interleukin (IL)-1 beta, IL-8, and IL-1 receptor antagonist in the hCG-induced rabbit ovulatory process. Administration of anti-IL-1 beta antiserum resulted in a reduction of the IL-1 receptor antagonist peak level. Administration of anti-IL-8 antiserum reduced the accumulation of IL-1 receptor antagonist.
Follicular-phase ovarian follicular fluid and plasma cytokine profiling ofnatural cycle invitro fertilization patients. Baskind NE 2014 et al.
To characterize follicular fluid (FF) and systemic cytokine profiles at various time points during the natural-cycle follicular and periovulatory phases.
Observational clinical study across two consecutive cycles.
Hospital-basedin vitro fertilization program.
Ten women undergoing modified natural-cycle invitro fertilization (MNC-IVF).
Plasma and follicular fluid (FF) collection.
MAIN OUTCOME MEASURE(S)
Forty FF cytokine concentrations from individual follicles and plasma from each patient were determined by fluid-phase multiplex immunoassay in two consecutive cycles: 1) tracking cycle-midfollicular or luteal surge; and 2) treatment cycle-periovulatory (at the time of MNC-IVF). Demographic, cycle, and cytokine data were compared with the use of chi-square, paired-scores t test, or Wilcoxon signed ranks tests.
Fluctuations in various FF cytokines were evident during the follicular phase: Levels of interleukin (IL) 6 and IL-8 were higher in periovulatory samples, and IL-1 receptor antagonist and vascular endothelial growth factor were elevated earlier in the cycle. Luteal surge profiles were similar to those found in periovulatory samples. Conversely, circulatory cytokine concentrations were more stable during the follicular phase.
These findings present an extensive physiologic reference profile of FF cytokines associated with antral folliculogenesis and highlight the compartmentalization of systemic and intraovarian cytokine networks in natural cycles.
In situ hybridization localized Il-1Ra to mural, antral, and cumulus granulosa cells. Modestly intense staining was also observed in oocytes (Kol et al, 1999).
Antral, Preovulatory, Corpus luteum
Mutation name: IL-1 RA
type: null mutation fertility: fertile Comment: Mice lacking IL-1ra have decreased body mass compared with wild-type controls. They are more susceptible than controls to lethal endotoxemia but are less susceptible to infection with Listeria monocytogenes. Conversely, IL-1ra overproducers are protected from the lethal effects of endotoxin but are more susceptible to listeriosis. Serum levels of IL-1 following an endotoxin challenge are decreased in IL-1ra nulls and increased in IL-1ra overproducers in comparison to controls. These data demonstrate critical roles for endogenously produced IL-1ra in growth, responses to infection and inflammation, and regulation of cytokine expression (Hirsch et al. 1996).