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HDAC7 modulates TNF-α-mediated suppression of Leydig cell steroidogenesis

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Abstract

The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) has an inhibitory role in gonadal functions particularly in the steroidogenesis of Leydig cells. In the present study, we demonstrate that TNF-α activates histone deacetylases 7 (HDAC7), which regulates the expression of steroidogenic enzyme genes in Leydig cells. LC-540 Leydig cells were treated with TNF-α (10 ng/ml) for different time intervals. TNF-α treatment significantly suppressed histone H3 acetylation and methylation and, concomitantly, increased the total histone deacetylases activity in LC-540 Leydig cells. RT-PCR and western blot analysis revealed that HDAC7 was up-regulated in TNF-α-treated cells. Our results also demonstrated that an siRNA-mediated knockdown of HDAC7 restores the expression of steroidogenic proteins in TNF-α-treated Leydig cells. These findings provide valuable information that TNF-α-mediated suppression of steroidogenesis involves HDAC7 in Leydig cells.

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Acknowledgments

The authors gratefully acknowledge Indian Council of Medical Research (ICMR), New Delhi, India, for the financial assistance. The infrastructure provided by DST-FIST is also gratefully acknowledged.

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Authors and Affiliations

  1. Department of Biochemistry, Bharathidasan University, Tiruchirappalli, 620 024, India

    Mohanraj Sadasivam, Balamurugan Ramatchandirin, Sivasangari Balakrishnan & Chidambaram Prahalathan

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  1. Mohanraj Sadasivam
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  2. Balamurugan Ramatchandirin
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  3. Sivasangari Balakrishnan
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  4. Chidambaram Prahalathan
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Corresponding author

Correspondence to Chidambaram Prahalathan.

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Supplementary Fig. 1

LC-540 cell viability is affected by TNF-α in a dose- (A) and time- (B) dependent manner. Values represent mean ± SD for three independent experiments (n = 3). Values are statistically significant at ***P < 0.001, **P < 0.01, and *P < 0.05. Supplementary material 1 (TIFF 153 kb)

Supplementary Fig. 2

Effect of TNF-α on histone H3 acetylation and methylation in acid-extracted histones of LC-540 Leydig cells. LC-540 Leydig cells were treated with or without TNF-α (10 ng/ml) for the indicated time intervals. The nuclear histones were extracted and used for the analysis. Total histone H3 levels were utilized as an internal control. Values represent mean ± SD for three independent experiments (n = 3). Values are statistically significant at ***P < 0.001, **P < 0.01, and *P < 0.05. Supplementary material 2 (TIFF 163 kb)

Supplementary Fig. 3

Effect of HDAC7 inhibition on Leydig cell steroidogenesis. LC-540 Leydig cells were pretreated with sodium butyrate (10 mM) for 60 min and then treated with or without TNF-α (10 ng/ml) and used for the analysis. A) Representative mRNA expression to show HDAC7 inhibition in LC-540 Leydig cells. B) Effect of HDAC7 inhibition on steroidogenic genes in LC-540 Leydig cells treated with or without TNF-α. β-actin levels were utilized as an internal control. Values represent mean ± SD for three independent experiments (n = 3). Comparisons are made between a—(control versus TNF-α treated), b—(control versus sodium butyrate treated), and c—(TNF-α versus sodium butyrate + TNF-α treated). Values are statistically significant at ***P < 0.001, **P < 0.01, ns non-significant. Supplementary material 3 (TIFF 195 kb)

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Sadasivam, M., Ramatchandirin, B., Balakrishnan, S. et al. HDAC7 modulates TNF-α-mediated suppression of Leydig cell steroidogenesis. Mol Cell Biochem 406, 83–90 (2015). https://doi.org/10.1007/s11010-015-2426-y

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