Altered expression of cytokines IL-1α, IL-6, IL-8 and TNF-α in bovine follicular persistence
Introduction
The production of cytokines in the ovary, their accumulation in ovarian follicular fluid, and their effect on some ovarian processes suggest that cytokines may be important autocrine and paracrine regulators of the ovarian functions [1], [2], [3], [4], [5]. Among cytokines, interleukins (ILs) appear to be involved in the control of numerous physiological and pathophysiological processes in the ovary and to be important regulators in the reproductive function [4]. The interleukin-1 (IL-1) system, which consists of IL-1α and IL-1β, is an important mediator of inflammation [6]. The IL1 system has several sites of synthesis in the ovary and IL1-like bioactivity has been reported in human, equine and porcine follicular fluid at the time of ovulation [7], [8]. IL-1 is involved in several ovulation-associated events, such as the synthesis of proteases, induction of gelatinases, regulation of plasminogen activator activity, and production of prostaglandins and nitric oxide [9], [10]. IL-1 also regulates ovarian steroidogenesis [11] and has effects on several pathways of the ovulatory cascade such as progesterone synthesis [12].
IL-6, a multifunctional cytokine, represents a physiological link between the endocrine and immune systems and is a modulator of the ovarian function [13], [14], [15]. IL-6 is produced by granulosa cells in preovulatory follicles at the time of ovulation [16]. Besides its extensively studied proinflammatory functions, IL-6 has been shown to have an anti-inflammatory function because it suppresses IL-1 and Tumor Necrosis Factor (TNF) synthesis and induces the production or release of IL-1 and TNF antagonists [17].
IL-8, from the group of α-chemokines, is involved in follicular development, atresia, ovulation, steroidogenesis, and corpus luteum function [18], [19]. In addition, IL-8 appears to be essential to gonadotropin-induced ovulation in the rabbit [20], [21] and is involved in angiogenesis, cell proliferation and apoptosis [22], [23], [24].
TNF-α may play a functional role in ovulation since it induces ovulation in the perfused rat ovary [25]. Also intra-follicular injection of TNF-α antiserum blocks ovulation in the sheep ovary [26]. TNF-α is a mediator of the immediate-early response and can promote ovarian cell proliferation and prostaglandin production [8], [18]. Also, this cytokine can promote ovarian cell proliferation and inhibit steroidogenesis in undifferentiated ovarian cells, and stimulate progesterone synthesis in differentiated ones [3], [8], [18], [27].
Cystic ovarian disease (COD) is one of the most important causes of reproductive failure in cattle [28] and a major factor contributing to poor reproductive efficiency of lactating dairy cows [29], [30], [31]. COD causes anovulation and continuous growth of follicles to excessive diameters over 20 mm, which fail to ovulate, thus persisting and then interfering with normal ovarian function [30], [31]. Anovulation of the dominant follicle is attributable to the lack of an LH surge resulting from endocrine imbalances [31]. Nevertheless, the persistence of follicles over time is also related to an intra-ovarian component [31], [32].
The study of the processes that lead to ovulatory failure and persistence of the dominant follicle is key to understand the pathogenesis of COD. However, due to the unpredictability of the occurrence of cysts, it is extremely difficult and often impractical to study their spontaneous development. Therefore, the use of experimental models for the study of the early events of cystogenesis is fundamental to understand the mechanisms involved in the pathogenesis of COD [33].
Considering the multiple factors involved in the ovulation process, we hypothesized that the alteration of some cytokines involved in this process may contribute to follicular persistence and therefore to the pathogenesis of COD in cows. Because ovarian cells represent sources and targets of various cytokines, the aim of this study was to examine IL-1α, IL-6, IL-8 and TNF-α expression in ovarian follicular structures during the development of follicular persistence induced in cows by long-term progesterone administration.
Section snippets
Animals
All the procedures were approved by the Institutional Ethics and Security Committee of the Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral, Santa Fe, Argentina (protocol N° 131/12), and are consistent with the “Guide for the Care and Use of Agricultural Animals in Research and Teaching, Third Edition” (Federation of Animal Science Societies, 2010). This study was performed in non-lactating Holstein cows (n = 25) with regular estrous cycles. The body condition score of
Experimental model
In treated animals, healthy developing follicles, follicles showing different degrees of atresia, and one large persistent follicle (in one ovary) with a complete granulosa cell layer were observed. No active corpus luteum was present. Ovaries from control animals exhibited follicles in various stages of development, including primary, preantral, and antral follicles, as well as atretic follicles and regressed corpora lutea. In addition, induction was confirmed by serum and FF hormone analysis
Discussion
The study of the processes that lead to ovulatory failure and persistence of the dominant follicle is the key to understand the pathogenesis of COD [33]. Previous studies have determined increased expression of proinflammatory cytokines in bovine cystic follicles, indicating that the expression of these proteins is altered and may be related to the persistence of follicular cysts [38].
In the present study, we found an altered expression of the cytokines evaluated. We examined the expression of
Conclusion
There is a growing body of evidence that supports the necessity of certain kinds of inflammatory responses in various reproductive events. Under physiological and pathophysiological conditions, cytokines seem to exert their pleiotropic activities in the reproductive system. The results of this study suggest a close relationship between the immune and the reproductive systems, showing their participation throughout ovarian folliculogenesis and, considering the experimental model, their
Competing interests
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Acknowledgments
This study was supported by a grant from the Argentine National Agency for the Promotion of Science and Technology (ANPCyT) (PICT 2011-1274). MEB, FR, HHO and NRS are Research Career Members and AFS, EMB, PUD and FMR are Fellows of the National Scientific Research Council (CONICET, Argentina). NCG and CJL are Fellows of ANPCyT. We are grateful to the staff of the Large Animal Health Hospital of the Facultad de Ciencias Veterinarias de la Universidad Nacional del Litoral (Santa Fe, Argentina)
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