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

Endocrinology. 2015 Sep;156(9):3192-202. doi: 10.1210/EN.2015-1238. Epub 2015 Jun 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Female
  • Follicle Stimulating Hormone
  • Gene Expression Regulation
  • Granulosa Cells / metabolism*
  • Histone Deacetylases / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Wistar
  • Receptors, LH / metabolism*
  • Transcription Factor RelA / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Receptors, LH
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Follicle Stimulating Hormone
  • Cyclic AMP
  • Proto-Oncogene Proteins c-akt
  • Histone Deacetylases