Changes in IL-16 Expression in the Ovary during Aging and Its Potential Consequences to Ovarian Pathology

Aging in females is not only associated with the changes in hormonal status but is also responsible for dysregulation of immune functions in various organs including ovaries. The goal of this study was to determine whether the expression of interleukin 16 (IL-16), a proinflammatory and chemoattractant cytokine, changes during ovarian aging, to determine factors involved in such changes in IL-16 expression, and to examine if changes in IL-16 expression during aging predisposes the ovary to pathologies. Ovarian tissues from premenopausal women (30-50 years old), women at early menopause (55-59 years old), and late menopause (60-85 years old) were used. In addition, tumor tissues from patients with ovarian high-grade serous carcinoma at early stage (n = 5) were also used as reference tissue for comparing the expression of several selected markers in aging ovaries. The expression of IL-16, frequency of macrophages (a source of IL-16) and expression of microRNA (miR) 125a-5p (a regulator of IL-16 gene) were performed by immunohistochemistry, immunoblotting, and gene expression assays. In addition, we examined changes in nuclear expression of IL-16 expression with regards to exposure to follicle-stimulating hormone (FSH) by in vitro cell culture assays with human ovarian cancer cells. The frequencies of IL-16 expressing cells were significantly higher in ovarian stroma in women at early and late menopause as compared with premenopausal women (P < 0.0001). Similar patterns were also observed for macrophages. Expression of miR-125a-5p decreased significantly (P < 0.001) with the increase in IL-16 expression during aging. Furthermore, expression of nuclear IL-16 increased remarkably upon exposure to FSH. Consequently, ovarian aging is associated with increased expression of IL-16 including its nuclear fraction. Therefore, persistent high levels of FSH in postmenopausal women may be a factor for enhanced expression of IL-16. Effects of increased nuclear fraction of IL-16 need to be examined.