Topical vitamin D3 analogues induce thymic stromal lymphopoietin and cathelicidin in psoriatic skin lesions

Sato, Emi; Imafuku, Shinichi; Chou, Bin; Ishii, Kazuya; Hiromatsu, Kenji; Nakayama, Juichiro

doi:10.1111/j.1365-2133.2012.10917.x

Cited by 44 publications

(56 citation statements)

References 50 publications

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“…These findings are consistent with epidemiological data suggesting that patients with allergic skin inflammation are protected from skin cancer (5)(6)(7)(8). TSLP expression and its immune effects in the skin can be induced by calcipotriol (calcipotriene), an FDA-approved topical medication for psoriasis (9)(10)(11). To determine the efficacy of TSLP induction as a novel immunotherapeutic approach for cancer, we investigated the effect of calcipotriol on skin carcinogenesis in genetically engineered mouse models and in patients with actinic keratosis.…”

Section: Introductionsupporting

confidence: 69%

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Cunningham

Tabacchi

Eliane

et al. 2016

Journal of Clinical Investigation

138

113

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Premalignant lesions of cutaneous squamous cell carcinoma (SCC) are identified clinically as actinic keratoses (12,13). Several field-directed treatments including 5-fluorouracil (5-FU), diclofenac, ingenol, and imiquimod have been approved for the treatment of sun-damaged skin with multiple actinic keratoses (13-15). However, the long treatment duration and the severity BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. METHODS.The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. RESULTS.Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4 + T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration.CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4 + T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs.TRIAL REGISTRATION. ClinicalTrials.gov NCT02019355. FUNDING. Not applicable (investigator-initiated clinical trial).

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Section: Introductionsupporting

confidence: 69%

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Cunningham

Tabacchi

Eliane

et al. 2016

Journal of Clinical Investigation

138

113

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“…Previous studies (38-42) have implicated CAMP/LL-37 in some autoimmune diseases, including skin disorders. LL-37 levels do not decline during successful treatment of psoriatic plaques and, in fact, increase when lesions are treated with topical vitamin D3 analogs (41). Furthermore, previous studies have indicated that LL-37 treatment may promote ovarian cancer (43) and lung cancer (44).…”

Section: Discussionmentioning

confidence: 97%

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

et al. 2015

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Cathelicidin antimicrobial peptide (CAMP) is a naturally occurring secreted peptide that is expressed in several organs with pleiotropic roles in immunomodulation, wound healing, and cell growth. We previously demonstrated that gut Camp expression is upregulated when type 1 diabetes–prone rats are protected from diabetes development. Unexpectedly, we have also identified novel CAMP expression in the pancreatic β-cells of rats, mice, and humans. CAMP was present even in sterile rat embryo islets, germ-free adult rat islets, and neogenic tubular complexes. Camp gene expression was downregulated in young BBdp rat islets before the onset of insulitis compared with control BBc rats. CAMP treatment of dispersed islets resulted in a significant increase in intracellular calcium mobilization, an effect that was both delayed and blunted in the absence of extracellular calcium. Additionally, CAMP treatment promoted insulin and glucagon secretion from isolated rat islets. Thus, CAMP is a promoter of islet paracrine signaling that enhances islet function and glucoregulation. Finally, daily treatment with the CAMP/LL-37 peptide in vivo in BBdp rats resulted in enhanced β-cell neogenesis and upregulation of potentially beneficial gut microbes. In particular, CAMP/LL-37 treatment shifted the abundance of specific bacterial populations, mitigating the gut dysbiosis observed in the BBdp rat. Taken together, these findings indicate a novel functional role for CAMP/LL-37 in islet biology and modification of gut microbiota.

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“…Sato-Deguchi et al (25) reported that hCAP-18/LL-37 mRNA expression is increased by treatment with OCT in the skin tissues from psoriasis patients. Taken together, these observations suggest that active metabolites of vitamin D induce hCAP-18/LL-37, which is capable of inducing innate immune defense and providing a promising therapeutic target involving gingival/oral epithelial cells against periodontal pathogen infection.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D3 analog maxacalcitol (OCT) induces hCAP-18/LL-37 production in human oral epithelial cells

et al. 2016

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Maxacalcitol (22-oxacalcitriol: OCT) is a synthetic vitamin D 3 analog with a limited calcemic effect. In this study, we investigated whether OCT increases the production of LL-37/CAP-18, a human cathelicidin antimicrobial peptide, in human gingival/oral epithelial cells. A human gingival epithelial cell line (Ca9-22) and human oral epithelial cell lines (HSC-2, HSC-3, and HSC-4) exhibited the enhanced expression of LL-37 mRNA upon stimulation with OCT as well as active metabolites of vitamins D 3 and D 2 . Among the human epithelial cell lines, Ca9-22 exhibited the strongest response to these vitamin D-related compounds. OCT induced the higher production of CAP-18 (ng/mL order) until 6 days time-dependently in Ca9-22 cells in culture. The periodontal pathogen Porphyromonas gingivalis was killed by treatment with the LL-37 peptide. These findings suggest that OCT induces the production of hCAP-18/LL-37 in a manner similar to that induced by the active metabolite of vitamin D 3 .

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Topical vitamin D3 analogues induce thymic stromal lymphopoietin and cathelicidin in psoriatic skin lesions

Abstract: Topical VD3As induce TSLP and cathelicidin in psoriatic lesions, resulting in suppression of IL-12/23 p40, IL-1α, IL-1β and TNF-α, thereby ameliorating psoriatic plaques.

Cited by 44 publications

References 50 publications

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

<b>Vitamin D</b><b><sub>3</sub></b><b> analog maxacalcitol (OCT) induces hCAP-18/LL-37 production in human oral epithelial </b><b>cells </b>

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