TLR2/EGFR Are Two Sensors for pBD3 and pEP2C Induction by Sodium Butyrate Independent of HDAC Inhibition

• Published in: Journal of agricultural and food chemistry Vol. 68; no. 2; pp. 512 - 522
• Main Authors: Dou, Xiujing, Gao, Nan, Lan, Jing, Han, Junlan, Yang, Yang, Shan, Anshan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.01.2020
• Subjects: Animals; beta-Defensins - genetics; beta-Defensins - metabolism; Butyric Acid - pharmacology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene Expression Regulation - drug effects; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Interleukin-18 - genetics; Interleukin-18 - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; Swine; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; sodium butyrate; expression; host defense peptides; epidermal growth factor receptor; toll-like receptor 2
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.9b06569

Host defense peptides (HDPs) are vital mucosal defense effectors of the innate immune response. The expression of HDPs is inducible in epithelial cells by potent endogenous inducers. Herein, our results demonstrate that sodium butyrate (NaB) induces the expression of porcine β-defensin-3 (pBD3) and porcine epididymis protein 2 splicing variant C (pEP2C) in a dose- and time-dependent manner, without modifying the production of proinflammatory cytokines, in porcine intestinal epithelial cells (IPEC J2). Moreover, NaB promotes toll-like receptor 2 (TLR2) expression. TLR2 silencing inhibits the pBD3 and pEP2C expression induced by NaB but does not abolish the histone deacetylase (HDAC) inhibitory activity of NaB. We found that NaB activated the nuclear factor-κB (NF-κB) pathway. Importantly, the degree of cell confluence governs the regulatory responses but does not affect the HDAC activity of NaB. Furthermore, epidermal growth factor receptor (EGFR), but not the mitogen-activated protein kinase (MAPK) pathway, is vital during the NaB-induced pBD3 and pEP2C regulation process. We also demonstrated that pBD3 overexpression increases interleukin-18 levels. This study showed that NaB simultaneously induces pBD3 and pEP2C via TLR2 and EGFR in IPEC J2 cells without increasing the risk of a harmful inflammatory response.