414 Both sphingosine kinase 1 and 2 coordinately regulate cathelicidin antimicrobial peptide production during keratinocyte differentiation

Abstract

The innate immune element, cathelicidin antimicrobial peptide (CAMP), is a vital antimicrobial peptide needed for the formation of the antimicrobial skin barrier. We recently identified a novel endoplasmic reticulum (ER) stress-mediated sphingosine-1-phosphate (S1P)-dependent mechanism of CAMP synthesis. Interestingly, in this study, we found that S1P synthesized by an isoform of sphingosine kinase (SPHK), SPHK1, serves as a signal for CAMP synthesis and conversely, another isoform (SPHK2) likely has a suppressor role in CAMP production. CAMP production is increased during epidermal differentiation and enriched in the stratum corneum. Pertinently, prior studies showed that physiological ER stress is essential for normal epidermal differentiation. We here investigated how CAMP production is increased during epidermal differentiation. We found that 1) increased ER stress is evident in differentiated cultured keratinocytes; 2) increases in both CAMP and S1P production depend upon differentiation level of keratinocyte (proliferatedwt, but not dominant negative SPHK2 suppresses CAMP production in both proliferated and differentiated KC. Our current study suggests that both an increase in SPHK1 and a decrease in SPHK2 expression coordinately stimulate CAMP production during epidermal differentiation.