Serum IL-1RA levels increase from follicular to luteal phase of the ovarian cycle: A pilot study on human female immune responses

The immune responses exhibited by females are distinct from those of males. Females are known to generate, among others, higher levels of antibodies, greater interferon responses, and increased levels of inflammatory mediators in response to pathogens. Mounting evidence suggests that gonadal hormones play a key role in these differences. To better understand the effect of cycling hormones on the immune response, we sought to investigate the relationship between gonadal hormone fluctuations during the ovarian cycle and the levels of interleukin 1β and IL-1RA, both in circulation and in PBMCs in response to TLR4 stimulation, in healthy premenopausal females. To do this we measured the gonadal hormones 17β-estradiol, progesterone, and luteinizing hormone, and the cytokines IL-1β and IL-1RA in nine cycling females at several time points throughout one complete cycle. We evaluated 35 follicular, 17 ovulatory, and 44 luteal time points in our cohort and found a clear increase in serum levels of anti-inflammatory IL-1RA in the luteal phase, as compared to the follicular phase, and a positive correlation between both 17β-estradiol and progesterone and IL-RA. There was no difference in the serum levels of IL-1β and no difference in IL-1 β or IL-1RA produced in response to LPS by PBMCs isolated from different phases. Division of the cycle into sub-phases revealed an increase in the level of IL-1RA by ovulation that persisted through the luteal phase. These data suggest that significant changes in the immune response occur throughout the ovarian cycle in healthy females.