title: Vitamin D-induced up-regulation of human keratinocyte cathelicidin anti-microbial peptide expression involves retinoid X receptor α.
abstract: The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3), has been reported to positively regulate the human cathelicidin anti-microbial peptide (CAMP) gene coding for LL-37, but the mechanisms are not completely understood. We have determined the expression of CAMP, vitamin D receptor (VDR), and the retinoid X receptor (RXR) isoforms in human skin and gingival tissue biopsies and investigated the signaling pathways involved in 1,25D3-induced upregulation of CAMP. Human skin and gingival biopsies exhibited few VDR-immunoreactive cells within the stratum basale, whereas rat colon enterocytes (positive control) possessed abundant VDR immunoreactivity. Nuclear VDR immunoreactivity was demonstrated in human skin keratinocytes (HaCaT cells). Gene analysis revealed that human skin biopsies expressed higher levels of both CAMP and RXRα mRNA than human gingival biopsies, whereas VDR and RXRβ transcript levels were similar in skin and gingiva. In HaCaT cells, treatment with 1,25D3 (5 nM and 1 μM) for 4 and 24 h up-regulated CAMP mRNA several fold, and treatment with 1,25D3 for 24 h increased protein expression of the pro-form of LL-37 (hCAP-18) by about 13 times. The 1,25D3-evoked stimulation of HaCaT CAMP expression was associated with attenuated VDR mRNA and protein expression. Treatment with RXRα short interfering RNA reversed the 1,25D3-induced CAMP expression in HaCaT cells, showing that RXRα is involved in the up-regulation of CAMP by 1,25D3. We conclude that the 1,25D3-evoked stimulation of CAMP expression in human skin keratinocytes is dependent on RXRα but is not associated with the up-regulation of VDR expression.
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC D12, SE-221 84, Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Svensson
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC D12, SE-221 84, Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nebel
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC D12, SE-221 84, Lund, Sweden.
authors.forename: Ulrikke
authors.initials: U
authors.lastname: Voss
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC D12, SE-221 84, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Ekblad
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC D12, SE-221 84, Lund, Sweden. bengt-olof.nilsson@med.lu.se.
authors.forename: Bengt-Olof
authors.initials: BO
authors.lastname: Nilsson
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D005881:Gingiva / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D054804:Cathelicidins
keywords: Cathelicidin; Keratinocyte; Retinoid X receptor; Vitamin D; Vitamin D receptor