Regulation of cathelicidin gene expression: Induction by lipopolysaccharide, interleukin-6, retinoic acid, and Salmonella enterica serovar typhimurium infection

Cathelicidins are a family of antimicrobial peptides prominent in the host defense mechanisms of several mammalian species. In addition to their antim icrobial activities, these peptides have been implicated in wound healing, angiogenesis, and other innate immune mechanisms. To investigate the regula tory mechanisms of cathelicidin gene expression, we conducted in vitro expe riments evaluating the bone marrow cell expression of two porcine cathelici dins, PR-39 and protegrin, and cloned and evaluated the promoter sequence o f PR-39. In addition, we evaluated in vivo kinetics of cathelicidin gene ex pression in pigs during an infection with Salmonella enterica serovar Typhi murium. Lipopolysaccharide (LPS) increased PR-39 and protegrin mRNA express ion, which was ameliorated by polymyxin B. Concentrations of PR39 in supern atants from bone marrow cell cultures were increased 10-fold after LPS stim ulation. Similarly, interleukin-6 (IL-6) and all-trans retinoic acid (RA) m arkedly induced cathelicidin gene expression. To verify the transcriptional activation of the PR39 gene by these agents, we made a PR-39 promoter-luci ferase construct containing the full-length PR-39 promoter driving lucifera se gene expression and transiently transfected PK-15 epithelial cells. RA a nd IL-6 increased luciferase activity in PK-15 cells transfected with the P R-39 promoter-luciferase reporter. Similarly, Salmonella-challenged pigs sh owed increased expression of PR-39 and protegrin mRNA in bone marrow cells at 6 and 24 h postchallenge. Taken together, these findings show that bacte rial products (LPS), IL-6, RA, and Salmonella infection enhance the express ion of the cathelicidins, PR-39 and protegrin, in bone marrow progenitor ce lls, and we suggest that extrinsic modulation of this innate host defense m echanism may be possible.