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

Abstract

Cathelicidin antimicrobial peptide (CAMP) is a key antimicrobial peptide in skin. CAMP production is increased during epidermal differentiation and enriched in the stratum corneum. We recently identified a novel endoplasmic reticulum (ER) stress-mediated sphingosine-1-phosphate (S1P)-dependent mechanism of CAMP synthesis. 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 or no role in CAMP synthesis. Pertinently, prior studies showed that physiological ER stress is essential for normal epidermal differentiation. We here show that: increased ER stress occurs in differentiated cultured keratinocytes (KC); 2) increases in both CAMP and S1P production depend upon differentiation level of KC (proliferated<early-<late-stage of differentiation); 3) expression of SPHK1 and SPHK2 is increased and decreased, respectively, during KC differentiation; and 4) dihydroS1P that is preferentially synthesized by SPHK2 does not increase CAMP production. Finally, overexpression of wild type, but not dominant negative SPHK2, suppresses CAMP production. Our study suggests that alterations of both SPHK1 and SPHK2 levels coordinately increase CAMP production during epidermal differentiation.