Sphingosine kinase-1 is required for toll mediated beta-defensin 2 induction in human oral keratinocytes.

PloS One
Manjunatha R BenakanakereDenis F Kinane

Abstract

Host defense against invading pathogens is triggered by various receptors including toll-like receptors (TLRs). Activation of TLRs is a pivotal step in the initiation of innate, inflammatory, and antimicrobial defense mechanisms. Human beta-defensin 2 (HBD-2) is a cationic antimicrobial peptide secreted upon gram-negative bacterial perturbation in many cells. Stimulation of various TLRs has been shown to induce HBD-2 in oral keratinocytes, yet the underlying cellular mechanisms of this induction are poorly understood. Here we demonstrate that HBD-2 induction is mediated by the Sphingosine kinase-1 (Sphk-1) and augmented by the inhibition of Glycogen Synthase Kinase-3beta (GSK-3beta) via the Phosphoinositide 3-kinase (PI3K) dependent pathway. HBD-2 secretion was dose dependently inhibited by a pharmacological inhibitor of Sphk-1. Interestingly, inhibition of GSK-3beta by SB 216763 or by RNA interference, augmented HBD-2 induction. Overexpression of Sphk-1 with concomitant inhibition of GSK-3beta enhanced the induction of beta-defensin-2 in oral keratinocytes. Ectopic expression of constitutively active GSK-3beta (S9A) abrogated HBD-2 whereas kinase inactive GSK-3beta (R85A) induced higher amounts of HBD-2. These data implicate S...Continue Reading

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Citations

Jun 17, 2011·Journal of Cellular Physiology·Chenming SunYong Zhao
Jun 3, 2015·The Journal of Endocrinology·Muneki IkedaSuguru Kawato
Feb 13, 2018·The Journal of Pharmacology and Experimental Therapeutics·Randy S SchrecengostCharles D Smith
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Apr 7, 2019·Molecular Immunology·Hellen TeixeiraManjunatha R Benakanakere

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Methods Mentioned

BETA
biopsies
transfection
ELISA
PCR

Software Mentioned

GraphPad Pism
GraphPad Instat

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