title: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Kohshiro
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kishi
authors.affiliation: Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Imai
authors.affiliation: Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Suwa
authors.affiliation: Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirakawa
authors.affiliation: Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Minegishi
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D011974:Receptors, LH / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D011974:Receptors, LH; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases