Regulation and induction of first line defences expression in human bronchial epithelial cell line VA10.
Antimicrobial peptides (AMPs) form an important part of innate immunity in humans and constitute the first line of defensive barrier against the invading microbes preventing infections. In our current study, we looked at the effect of histone deacetylase inhibitor 4- phenyl butyric acid (PBA) on innate immune effectors and associated regulatory pathways in a human bronchial epithelial cell line VA10. PBA significantly induced expressions of several innate effectors pro-LL-37(cathelicidin), DEFB1 (human beta defensin 1) and others in a time and dose dependent manner. In addition PBA significantly enhanced Toll like receptor 5 ligand flagellin mediated pro-inflammatory cytokine expression. This activation was shown dependent on activation of MAP kinases. Further modulation of nuclear receptors differentially affected PBA induction of CAMP expression in an unexpected way. We also show effect of PBA on enzymes of the vitamin D metabolic pathway affecting cathelicidin regulation. Antimicrobial peptides have been indicated as effectors of wound healing. TGFB1, EGFR and transcription factors of cell differentiation affected PBA induced LL-37 expression. This indicates a cross talk between pathways involved in growth and differentiation with innate immune regulation. Finally we have shown PBA and Vitamin D3 induced antibacterial activity. Our future goal is to understand detailed mechanism behind PBA induced antimicrobial effectors identifying both cis and trans factors involved in regulation and ultimately strengthening the use of PBA as a therapeutic drug against infections.