These results reveal that IL-1/IL-1R1, IL-33/IL-33R and associated downstream signaling molecules are involved in the pathogenesis of endometriosis, and may provide novel therapeutic targets for endometriosis.
The impairment of the IL-1 family cytokine-network may lead to changes in the activation of immune system in the peritoneal cavity of women with endometriosis.
A known dysmenorrhea signal near NGF replicated in our data (rs12030576; P = 1.1 × 10<sup>-19</sup>) and was associated with RP4-663N10.1 expression, a putative lncRNA enhancer of NGF, while a novel dysmenorrhea signal in the IL1 locus (rs80111889; P = 1.9 × 10<sup>-16</sup>) contained SNPs previously associated with endometriosis, and GWAS SNPs were most significantly associated with IL1A expression.
We sought to further investigate the eight IL1A SNPs for association with endometriosis using an independent sample of 3908 endometriosis cases and 8568 controls of European and Japanese ancestry.
Association of rs6542095 at the IL1A locus with 'All' (p = .066) and 'Grade_B' (p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population.
Lower circulating levels of sIL1RAP points to a significant impairment in the counter-regulatory mechanisms of IL1, which in view of the cytokine's potent inflammatory and growth-promoting properties may play a significant role in the pathophysiology of endometriosis.
The four common variants (rs17561, rs1304037, rs2856836 and rs3783553) in IL1A were significantly associated with endometriosis (P=0.0024, 0.0024, 0.0014 and 0.0061, respectively).
In this case-control study, the IL-1α -889C>T, IL-1 receptor antagonist (IL-1RA) 86-bp microsatellite, IL-1 receptor 1 (IL-1R1) 52C>A, 294C>T, 1498T>C, 1632A>G, IL-1R2 rs2072472 C>T and rs7561460 C>T polymorphisms were analyzed in women with (n = 138) and without (n = 214) endometriosis using restriction fragment length polymorphism (RFLP) analysis, TaqMan assay, or DNA sequencing.
This points to a deficiency in the local control of IL-1 that, in view of the cytokine's elevated levels and potent proinflammatory, angiogenic, and growth-promoting effects, may contribute to endometriosis development.
In view of the wide spectrum of IL-1 inflammatory and growth-promoting effects, downregulation of sIL1RAcP, which is known for inhibiting IL1, indicates a profound defect in the capability of endometrial cells of women with endometriosis to counterregulate IL-1 effects and may represent an important mechanism underlying the ability of these cells to implant and develop into host tissues.
Interleukin 1 (IL1) may play an important role in endometriosis-associated pelvic inflammation, and natural specific inhibitors, including soluble IL1 receptor accessory protein (sIL1RAcP) and soluble IL1 receptor type 2 (sIL1R2), are critical for counterbalancing the pleiotropic effects of IL1.
Of note, four of the top five SNPs with P-values <10(-5) were located in and around IL1A (interleukin 1α), which might be a functional candidate gene for endometriosis.
This study revealed an imbalance between IL1beta and its decoy inhibitory receptor type 2 in women with endometriosis, which was particularly obvious in those who were infertile, and suggests that a defect in the local control of IL1 may be involved in the pathophysiology of endometriosis and related infertility.
The decrease in IL1R2 mRNA levels in eutopic endometrial tissue of endometriosis women, and the concomitant increase in IL1R1 mRNA levels in ectopic implants, reveal a profound defect in IL1R 1 and IL1R2 gene expression which may accentuate the capability of this tissue to respond to IL1 and favor its ectopic growth.
To assess the ability of peripheral blood serum from women with endometriosis to induce monocyte chemotactic protein-1 (MCP-1) secretion by monocytes and the putative role of the interleukin-1 (IL-1) system in endometriosis-associated monocyte activation.
The reduced levels of IL-1RII mRNA in the endometrium of women suffering from endometriosis reveals a profound defect in IL-1RII gene expression and, consequently, a reduced capability of endometrial tissue to down-regulate IL-1 activity.
IL-1 alpha mRNA was expressed by seven of 10 patients with endometriosis but by only one of the control group; this was again significantly different (P < 0.04).
Our results suggest that peritoneal macrophages express IL-1ra mRNA rather than IL-1 beta mRNA with the progress of endometriosis and that peritoneal macrophages may secrete IL-1ra protein that modulates the effects of IL-1.