Cytokine expression during different phases of the menstrual cycle

King, Christine April (1998) Cytokine expression during different phases of the menstrual cycle. Masters thesis, Memorial University of Newfoundland.

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Abstract

Previous studies have shown that cultured and circulating cells from women may differ in immune responses, the differences relating to the phase of the menstrual cycle in which they were harvested. In this investigation, specific enzyme-linked immunosorbent assays for IL-2, IL-4, IFNγ, IL-1ra and IL-1β were used to determine if there are differences in levels of cytokine expression at different phases of the menstrual cycle. -- A sample set of mononuclear cells and serum were isolated from nine healthy, cycling females (19-29 years) at known points in their cycle and from four male controls. The gonadal hormones 17β-estradiol, progesterone and luteinizing hormone, as well as serum cytokine levels and cytokine production by unstimulated and stimulated cells in culture were monitored. Results indicated that the levels of all the cytokines measured varied in relation to the menstrual cycle. IL-2, IL-4, and IFNγ secretion by PHA stimulated PBMC was low at time of ovulation and high in the luteal phase of the menstrual cycle. There appears to be a TH1 to TH2 shift from the follicular to the luteal phase. Secretion of IL-1β and IL-1ra in LPS stimulated cultures changed during the menstrual cycle. The IL-1 ratio (IL-1β/IL-1ra) was low at ovulation in unstimulated cultures and low at the late follicular and the midluteal phases of the cycle in LPS stimulated cultures. The IL-1 ratio in serum was lowest at ovulation with higher levels in the follicular and luteal phases. Variability in the levels of the cytokines detected in successive samples, both in serum and in culture supernatants, was greater for women than men for IL-4, IFNγ in culture supernatants, and for IL-1ra and IL-1β in serum. In addition, females had significantly higher mean values for IL-1ra in nonstimulated cultures and lower mean IL-1 ratios in serum as compared to males. Finally, multiple regression analysis of the cytokine data with the hormones estrogen, progesterone, and luteinizing hormone as well as with age of the volunteer, day in the cycle the sample was obtained, length of cycle, and day of ovulation demonstrated that IL-4 and possibly IFNγ production by stimulated PBMC and IL-1ra production by unstimulated PBMC are positively correlated with age. In contrast, IL-2, production by stimulated PBMC and serum levels of IL-1ra and IL-1β are negatively correlated with age. IL-1ra secreted by both stimulated and nonstimulated cells is positively correlated with day in the cycle the sample is taken whereas IL-1β correlates with day of ovulation and length of cycle. All of the correlations that were found to be significant in this study suggest that the menstrual cycle has a marked effect on the levels of cytokine production as detected in vivo in serum samples and in vitro in the supernatants of cells in culture. -- In summary, these data demonstrate that a) there is greater variation over time in amounts of cytokine produced by women than by men b) there are changes in cytokine production in women related to the menstrual cycle c) the lowest cytokine production occurs at time of ovulation (the exception being IL-1 in stimulated cultures) and d) age influences the amounts of cytokines produced by women. -- The data presented here support the hypothesis that (i) there are cyclical changes in immune responses in women (ii) the immune response is influenced by changes in hormone status and (iii) regulation of cytokine production is fundamentally different in women than men.

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