TNF-α Suppressed FSH-Induced LH Receptor Expression Through Transcriptional Regulation in Rat Granulosa Cells

Abstract

Several inflammatory cytokines regulate ovarian function. TNF-α is produced in granulosa cells under physiological conditions and has a reciprocal action on follicle development. In contrast, in pelvic inflammatory diseases, TNF-α is excessively produced in the pelvic cavity and has an adverse effect on reproductive functions. The objective of this study was to elucidate the mechanism of action of TNF-α on the expression of LH receptor (LHR) in immature rat granulosa cells. TNF-α suppressed FSH-induced LHR mRNA and protein expression and was not associated with cAMP accumulation. By using a luciferase assay, the construct containing base pairs -1389 to -1 of the rat Lhcgr promoter revealed that TNF-α decreased FSH-induced promoter activity. In response to TNF-α, nuclear factor (NF)-κB p65 was translocated to the nucleus, and the suppressive effect of TNF-α on LHR mRNA expression was abrogated by an NF-κB inhibitor. In a chromatin immunoprecipitation assay, TNF-α induced the association of NF-κB p65 with the rat Lhcgr transcriptional promoter region. NF-κB p65 and histone deacetylase (HDAC) interact to mediate expression of several genes at a transcriptional level. HDAC activity is thought to induce tight connections within local chromatin structures and repress gene transcription. Furthermore, the TNF-α-induced suppression of LHR mRNA expression was blocked by an HDAC inhibitor. Taken together, these results suggest that the interaction of NF-κB p65 with HDAC in the promoter region of rat Lhcgr might be responsible for TNF-α action on the regulation of LHR.

The estrogen–macrophage interplay in the homeostasis of the female reproductive tract

“…In fact, ovulation has been described as an inflammatory event that mainly enrolls inflammatory macrophages, which sustain the infiltration of additional immune cells, tissue disruption and subsequent maturation and functional specialization of granulosa cells through the secretion of inflammatory mediators (i.e. chemokines, reactive nitrogen species, prostaglandin F 2α ) and matrix remodeling enzymes (Espey, 1980;Machelon et al, 1995;Nakao et al, 2015;Shkolnik et al, 2011;Wong et al, 2002). Macrophage-derived signals are also important for vessel integrity of the antral follicle and corpus luteum, since whole body ablation of macrophages results in hemorrhage limitedly to the ovaries and not other tissues (Care et al, 2013;Turner et al, 2011).…”

Changes in the IGF-1 and TNF-α synthesis pathways before and after three-month reduction diet with low glicemic index in women with PCOS

“…7 mm in diameter, one of the follicles becomes a dominating one and develops further, whereas others die through apoptosis initiated by TNF-α in granulosa cells [30]. Thus, TNF-α has a protective function in ovary ageing because it drastically reduces FSH at the gene transcription level [31] and inhibits the synthesis of oestrogens [32].…”

The impact of adipose tissue-derived factors on the hypothalamic-pituitary-gonadal (HPG) axis

“…The latter association was much stronger when BMI was also taken into account. 17 A direct link between TNFa and the HPG axis has been established in animal models where TNFa exerted a transcriptional suppression of FSH-induced LH receptor 18 and direct effects on LH secretion. 19 Similarly, adipokines also exert a direct effect on components of the HPG axis.…”