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.

The host defense peptide LL‐37 is detected in human parotid and submandibular/sublingual saliva and expressed in glandular neutrophils

“…The pro‐form, hCAP18, is processed extracellularly to produce LL‐37 in a reaction catalyzed by either serine protease 3 or kallikrein 5 . Interestingly, vitamin D up‐regulates the cathelicidin‐related antimicrobial peptide ( CAMP ) gene that encodes LL‐37, suggesting that vitamin D modulates the innate immune system through this mechanism . The antimicrobial activity of LL‐37 is thought to be exerted through different mechanisms.…”

Role of serum 25‐hydroxyvitamin D levels and vitamin D receptor gene polymorphisms in patients with rosacea: a case–control study

“…Serum 1,25(OH) 2 D 3 has significant effects on the innate and adaptive immune systems by regulating expression of antimicrobial peptides (AMPs); in keratinocytes, the main one is cathelicidin . The effects of 1,25(OH) 2 D 3 on cathelicidin expression in human keratinocytes is based on RXR but is not related to the upregulation of VDR expression . Cathelicidin expression and function is changed in some inflammatory skin disorders and in rosacea .…”

“…Subsequently, vitamin D 3 is turned into an active form identified as 25‐hydroxyvitamin D 3 [25(OH)D 3 ], the serum form that is monitored to determine the vitamin D status of patients. However, the final and biologically active form, 1,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], exerts its actions through nuclear vitamin D receptors (VDR) and Retinoid X receptors (RXRs) on target cells …”

“…However, the final and biologically active form, 1,25dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], exerts its actions through nuclear vitamin D receptors (VDR) and Retinoid X receptors (RXRs) on target cells. 5,6 Serum 1,25(OH) 2 D 3 has significant effects on the innate and adaptive immune systems by regulating expression of antimicrobial peptides (AMPs); in keratinocytes, the main one is cathelicidin. 5 The effects of 1,25(OH) 2 D 3 on cathelicidin expression in human keratinocytes is based on RXR but is not related to the upregulation of VDR expression.…”

“…5 The effects of 1,25(OH) 2 D 3 on cathelicidin expression in human keratinocytes is based on RXR but is not related to the upregulation of VDR expression. 6 Cathelicidin expression and function is changed in some inflammatory skin disorders and in rosacea. 7 In patients with rosacea, the facial skin contains high levels of cathelicidin.…”