Abstract
Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.
Highlights
Natural aging is concomitant with a systemic low-grade chronic inflammation that contributes to age-related morbidity and mortality [1]
With the goal of investigating how parity modulates chronic, age-related systemic inflammation and how that modulation contributes to Ovarian cancer (OC) risk at menopause, we describe a profile of circulating hormones and cytokines in multiparous versus virgin C57BL/6 female mice subjected to tumor induction at peri-estropausal age
Because the age-dependent high levels of IL-10, IL4 and IL-5 were subsequently decreased by tumor induction only in multiparous mice in the present model, we suggest that parity during fertile life might improve antitumor immunity in aged mouse challenged with tumor-inducing cells
Summary
Natural aging is concomitant with a systemic low-grade chronic inflammation that contributes to age-related morbidity and mortality [1]. The gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH) typically increase at menopause due to impairment of the hypothalamic-pituitary-gonadal (HPG) axis and, importantly, have been proposed to play a role in OC pathogenesis [19]. Extending this link, plasma levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were positively correlated with circulating FSH in premenopausal women [5]. With the goal of investigating how parity modulates chronic, age-related systemic inflammation and how that modulation contributes to OC risk at menopause, we describe a profile of circulating hormones and cytokines in multiparous versus virgin C57BL/6 female mice subjected to tumor induction at peri-estropausal age. Our results suggest that parity supports and extends the host immune response against intraperitoneal OC tumor spread during menopause
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