Cytokine (IL16) and tyrphostin actions on ovarian primordial follicle development

Abstract

An ovarian follicle is composed of an oocyte and surrounding theca and granulosa cells. Oocytes are stored in an arrested state within primordial follicles until they are signaled to re-initiate development by undergoing primordial to primary follicle transition. Previous gene bionetwork analyses of primordial follicle development identified a number of critical cytokine signaling pathways and genes potentially involved in the process. In the current study, candidate regulatory genes and pathways from the gene network analyses were tested for their effects on the formation of primordial follicles (follicle assembly) and on primordial follicle transition using whole ovary organ culture experiments. Observations indicate that the tyrphostin inhibitor BCI increased follicle assembly significantly, supporting a role for the mitogen activated protein kinase (MAPK) signaling pathway in follicle assembly. The cytokine interleukin 16 (IL16) promotes primordial to primary follicle transition as compared to the controls, where as Delta-like 4 (DLL4) and WNT-3A treatment have no effect. Immunohistochemical experiments demonstrated for both the cytokine IL16 and its receptor CD4 localization to the granulosa cells surrounding each oocyte within the ovarian follicle. The tyrphostin LDN193189 (LDN) is an inhibitor of the bone morphogenic protein receptor 1 (BMPR1) within the TGFB signaling pathway and was found to promote the primordial to primary follicle transition. Observations support the importance of cytokines (i.e. IL16) and cytokine signaling pathways in regulating early follicle development. Insights into regulatory factors affecting early primordial follicle development are provided that may associate with ovarian disease and translate to improved therapy in the future.

Primary oocytes with cellular senescence features are involved in ovarian aging in mice

“…This observation is consistent with the new role of cellular senescence in causing apoptosis in senescent cells autonomously and neighboring cells through SASP [30]. Previous studies found that several cytokines, including interleukin 16 (IL16), IL6, IL18, and TNFα cause primordial follicle loss or activation [59][60][61]. We found that senescent primary oocytes produced IL1a and IL6; whether these two SASP cytokines cause primary oocyte loss will be investigated in our future study.…”

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

“…Numerous regulators that induce follicle activation have been identified including KITligand, epidermal growth factor, fibroblast growth factor 2 and 7, platelet-derived growth factor, bone morphogenetic protein 4 and 7, growth and differentiation factor 9, neurotrophin 3, brain-derived neurotrophic factor, glial-derived neurotrophic factor, insulin, interleukin 16, leukaemia inhibitory factor and gremlin (Dole et al 2008, Adhikari & Liu 2009, McLaughlin & McIver 2009, Nilsson et al 2009, Feeney et al 2014. The inhibitors of primordial activation that have been described to date include CXCL12, oestradiol, growth hormone, Hippo signalling and AMH (Adhikari & Liu 2009, McLaughlin & McIver 2009, Hsueh et al 2015.…”

Impacts of endometrioma on ovarian aging from basic science to clinical management

“…The pivotal role of IL-1 in regulating folliculogenesis and the positive effect of IL-1β on the activation of primordial follicles were verified in in vitro culture system of the bovine ovary ( 97 ). The IL-16 promotes primordial follicle activation and development during in vitro culturing of the rat ovarian tissue ( 98 ). Recently, in an animal model of ovarian aging, the cytokines including IL-6, IL-8, and TNF-α were proved to contribute to the depletion of ovarian reserve ( 99 ).…”