Interleukin-8 expression and modulation in human preovulatory follicles and ovarian cells.

Abstract

Just before the time of ovulation, the number of neutrophils increases markedly in the thecal layer of the leading follicle. A preovulatory rise in chemotactic activity for neutrophils in human follicular fluid has also been detected. We hypothesized that interleukin-8 (IL-8), a neutrophil chemoattractant/activating factor and a potent angiogenic agent, may be an important modulator of leukocyte chemotaxis in ovulatory function. In this regard we investigated the expression and modulation of IL-8 in human follicular fluid samples from patients undergoing in vitro fertilization-embryo transfer therapy and in ovarian stromal and granulosa-lutein cell cultures. The concentration of IL-8 in pre-hCG follicular fluid samples (n = 4) was 16 +/- 12 (mean +/- SEM) pg/ml, and that in post-hCG samples (n = 101) was 262 +/- 45 pg/ml (P = 0.001). In post-hCG samples, the concentration of IL-8 in an individual follicle correlated with the size of that follicle (r = 0.61; P = 0.02). We also observed a correlation between serum IL-8 levels (22 +/- 3 pg/ml) and follicular fluid levels (303 +/- 143 pg/ml), with a 14-fold gradient (r = 0.71; P = 0.01) in 11 patients tested for both. IL-8 messenger RNA (mRNA) and the protein were expressed constitutively in ovarian stromal cell cultures, and the level was increased by IL-1 alpha and tumor necrosis factor-alpha in a time- and concentration-dependent manner. hCG and LH induced higher levels of IL-8 mRNA expression and protein production. Granulosalutein cells also expressed IL-8 mRNA and protein, and the levels were increased by IL-1 alpha and tumor necrosis factor-alpha. Importantly, progesterone suppressed both basal and IL-1 alpha-stimulated IL-8 expression in stromal and granulosa-lutein cell types. In summary, we found that IL-8 levels are elevated in periovulatory follicular fluid, and both granulosa-lutein and ovarian stromal cells express the mRNA and produce the protein. The modulation of IL-8 in these cell cultures by steroid and trophic hormones suggests that IL-8 may play an important role in the physiology of ovulation, such as timely follicular rupture and neovascularization of the corpus luteum.

Endometriosis and Infertility: A Multi‐cytokine Imbalance Versus Ovulation, Fertilization and Early Embryo Development

“…The first is via prostaglandins which, by increasing vascular permeability, facilitate the follicular rupture and the second is via nitrogen oxide (NO) leading directly to follicular rupture. By the same token, TNF-a and IL-1b stimulate production of GM-CSF and IL-8, cytokines that will further facilitate ovulation and embryo implantation (Arici et al 1996). At that stage, IL-6 and IFN-g are also being detected in the endometrium possibly accounting for NO production .…”

Expression of cytokine‐induced neutrophil chemoattractant suppresses tumor necrosis factor alpha expression and thereby prevents the follicles from undergoing atresia and apoptosis

“…It has been shown that neutrophils accumulate in the theca layer of the ovaries in humans and rats just prior to ovulation and that the expression of IL‐8 and CINC/gro, respectively, are responsible for this accumulation 4, 7, 8. Earlier reports have shown that IL‐8 and CINC/gro production are enhanced by human chorionic gonadotropin (hCG) 5, 9, 10. It also has been reported that CINC/gro production is increased by the addition of IL‐1 beta and tumor necrosis factor (TNF) alpha to cultures of whole ovarian dispersates 5…”

Association between follicular fluid levels of HMGB1 protein and outcomes in patients undergoing in vitro fertilization/intracytoplasmic sperm injection cycles

“…Thus, ovulation is a well-recognized inflammatory process that is putatively modulated by cytokines. Numerous studies have demonstrated that a variety of proinflammatory cytokines, including interleukin (IL)-6, IL-8, IL-11, tumor necrosis factor (TNF)-α, leukemia inhibiting factor and the IL-1 system, are crucially involved in folliculogenesis (12), implantation (13) and follicular maturation (14)(15)(16).…”