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

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.