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Assessment of serum levels of cathelicidin and vitamin D in acne vulgaris

El-Ramly, Amany Z.; Fawzi, Marwa M.T.; Mahmoud, Sara B.; Abdel Ghaffar, Mariam M.; Shaker, Olfat G.

Journal of the Egyptian Women's Dermatologic Society: May 2016 - Volume 13 - Issue 2 - p 99–105
doi: 10.1097/01.EWX.0000480714.99599.84
Original articles
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Background Antimicrobial peptides, including cathelicidin, play a dual role in acne vulgaris: a protective role by acting against Propionibacterium acnes, or a proinflammatory role by acting as signaling molecules. Vitamin D is an important regulator of cathelicidin expression.

Objective To evaluate serum levels of cathelicidin and vitamin D in a group of Egyptian patients with acne vulgaris in comparison with controls, to explore the complex relationship between them and shed more light on their possible role in the pathogenesis of acne vulgaris.

Patients and methods This study included 60 patients with acne vulgaris and 60 healthy controls. Blood samples were obtained from all participants for the estimation of serum levels of cathelicidin and vitamin D using enzyme-linked immunosorbent assay.

Results The study revealed a significantly higher serum cathelicidin levels in acne patients compared with controls. Serum vitamin D levels were lower in acne patients compared with controls, with no significant difference. There was a statistically significant negative correlation between serum vitamin D and serum cathelicidin in both groups.

Conclusion Significantly higher serum cathelicidin levels were detected in acne patients compared with controls, suggesting that cathelicidin may play a role in the pathogenesis of acne vulgaris and may provide a possible therapeutic target for future treatment. In addition, lower (although nonsignificant) serum vitamin D levels were detected in patients, suggesting a possible role for vitamin D supplementation in acne treatment.

Departments of aDermatology

bBiochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt

Correspondence to Sara B. Mahmoud, MD, 16 El Shaheed Abd El Moneim Hafez Street, Almaza, Heliopolis, Cairo 11341, Egypt Tel: +20 010 018 28819; e-mail: bahaa.sara@yahoo.com

Received November 9, 2015

Accepted December 24, 2015

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Introduction

Acne is a common chronic inflammatory disease of the pilosebaceous unit, resulting from androgen-induced increased production of sebum, together with altered keratinization, inflammation, and bacterial colonization of hair follicles by Propionibacterium acnes1.

The innate immune system recognizes P. acnes by toll-like receptor 2 (TLR-2), leading to the secretion of inflammatory cytokines [interleukin (IL)-8 and IL-12] and antimicrobial peptides (AMPs, human β defensins, and cathelicidins) 2.

AMPs, including cathelicidin, may play a beneficial role in acne vulgaris by acting against P. acnes, or may promote inflammation through several immunomodulatory actions 3. Cathelicidins are a family of small cationic AMPs; only one of them is expressed in humans, hCAP18 (human cationic AMP), which is subsequently cleaved to yield the LL-37, its active molecule 4,5.

Vitamin D is a fat-soluble steroid hormone, which plays an important role in calcium homeostasis, immune system regulation, and cell growth and differentiation. The main source of vitamin D is synthesis in the skin upon sun exposure, and a small proportion is obtained from dietary sources 6,7.

Sebocytes were identified as bioactive vitamin D-responsive target cells, suggesting a possible role for vitamin D in acne 8. In addition, vitamin D enhances innate immunity by modulating production of AMPs and cytokine response 9.

Vitamin D has emerged as an important regulator of cathelicidin expression, as the encoding gene contains a vitamin D response element present in its promoter 10. Moreover, studies revealed that vitamin D increased the transcription of cathelicidin in the epithelial and mononuclear cells under in-vitro conditions 11,12.

The objective of this study was to evaluate serum levels of cathelicidin and vitamin D in a group of Egyptian patients with acne vulgaris in comparison with controls, in an attempt to explore the complex relationship between these two molecules and shed more light on their possible role in the pathogenesis of acne vulgaris.

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Patients and methods

The present case–control study included 60 patients with acne vulgaris and 60 age and sex matched controls recruited from the Dermatology Outpatient Clinic of Kasr El Aini Hospital, Cairo University. The Dermatology Research Ethical Committee, Faculty of Medicine, Cairo University approved the study, and signed informed consent was obtained from all participants, or from their legal guardians for those younger than 18 years. This study was conducted during the period from April to June 2015. Participants were recruited at approximately the same time to minimize the differences of seasonal changes in the value of vitamin D.

All participants were Egyptians between 15 and 35 years of age with Fitzpatrick skin types III and IV. Patients with other forms of acne, such as acne conglobata and acne fulminans, were not included in the study. Other exclusion criteria for patients and controls were as follows: any associated disease that alters serum vitamin D levels, such as vitiligo, psoriasis, other autoimmune diseases and renal diseases, pregnancy and lactation, topical use of vitamin D analogs and vitamin D supplementation, or receiving phototherapy during the last 3 months.

For all patients, full history was taken, including onset, course and duration of the disease, previous treatment, and family history of similar condition. In addition, patients and controls were questioned about any medical or dermatological diseases that could affect serum vitamin D levels. All participants were asked about adequacy of sun exposure, which was considered as unprotected noon time exposure for 5 min daily in fair-skinned individuals, or 10 min daily for dark-skinned individuals of more than 5% of the body surface area (the arms and legs or the hands, arms and face, two or three times/week) 13. For veiled women, adequate sun exposure was considered as unprotected noon time exposure for 10 min daily in fair-skinned individuals or 20 min daily in dark-skinned individuals of the hands and face, two or three times per week.

Dermatological examination included anatomical sites, type of lesions, and severity of acne according to the acne scoring system established by Lehmann et al.14.

A volume of 3 ml of venous blood sample was collected in a vacuum tube under sterile conditions from each participant for the detection of serum levels of cathelicidin and 25 hydroxyvitamin D [25(OH)D], the most indicative form of vitamin D level in the body 15. Vitamin D status was defined as follows: deficient, <20 ng/ml; insufficient, 20–29 ng/ml; and sufficient, >29 ng/ml 16.

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Measurement of serum cathelicidin using enzyme-linked immunosorbent assay

ELISA is an enzyme-linked immunosorbent assay for the quantitative detection of human cathelicidin in cell culture supernatants, plasma (heparin and citrate), serum, and other body fluids. The kit was provided by DRG International Inc. (Springfield, New Jersey, USA).

This assay uses an antibody specific for human cathelicidin coated on a 96-well plate. Standards, samples, and biotinylated anti-human cathelicidin are pipetted into the wells, and cathelicidin present in a sample is captured by the antibody immobilized to the wells and by the biotinylated cathelicidin-specific detection antibody. After washing away unbound biotinylated antibody, horseradish peroxidase-conjugated streptavidin is pipetted to the wells. The wells are again washed. Following this second wash step, tetramethylbenzidine substrate solution is added to the wells, resulting in color development proportional to the amount of cathelicidin bound. The intensity of the color is measured at 450 nm.

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Measurement of serum vitamin D using enzyme-linked immunosorbent assay

Vitamin D was measured in the sera of all patients and controls using human 25(OH)D ELISA kit provided by Sunredbio, Shanghai, China. The kit uses a double-antibody sandwich ELISA to detect human 25(OH)D in human samples.

25(OH)D was added to monoclonal antibody enzyme well, which is precoated with human 25(OH)D, and incubated. Subsequently, 25(OH)D antibodies labeled with biotin were added and combined with streptavidin–horseradish peroxidase to form an immune complex, and then incubation and washing were carried out again to remove the uncombined enzyme. Thereafter, chromogen solutions A and B were added, and the color of the liquid changed to blue. The concentration of the human substance 25(OH)D of sample was positively correlated. The vitamin D concentrations in sera were determined from the standard curve.

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Statistical analysis

Data were statistically described in terms of mean±SD or median and range for quantitative data, or frequencies (number of cases) and percentages for categorical data. Comparison of numerical variables between the study groups was made using the Student t-test for independent samples in comparing two groups when normally distributed and the Mann–Whitney U-test for independent samples when non-normally distributed. Comparison of normally distributed numerical variables between more than two groups was made using one-way analysis of variance test with post-hoc multiple two-group comparisons, whereas the Kruskal–Wallis test was used for non-normal data. For comparing categorical data, the χ2-test was performed. An exact test was used instead when the expected frequency was less than 5. Correlation between various variables was made using Pearson moment correlation equation for linear relation in normally distributed variables and using Spearman rank correlation equation for non-normal variables/nonlinear monotonic relation. Accuracy was presented using the terms sensitivity and specificity. Receiver operator characteristic analysis was used to determine the optimum cut-off value for the studied diagnostic markers. P values less than 0.05 were considered statistically significant. All statistical calculations were carried out using computer program SPSS (SPSS Inc., Chicago, Illinois, USA) release 15 for Microsoft Windows (2006).

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Results

The present study included two groups: 60 patients with acne vulgaris and 60 normal controls. The clinical data and laboratory findings of the two groups are presented in Table 1.

Table 1

Table 1

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Comparison between the two groups

Serum cathelicidin was significantly higher in acne patients compared with controls (P<0.001), with a mean level of 19.1±7.565 and 8.4±2.46 ng/ml in patients and controls, respectively (Fig. 1), whereas serum vitamin D showed no statistically significant difference (P=0.226), with a mean level of 28.7±10.65 and 32±18.15 ng/ml in patients and controls, respectively (Fig. 2).

Figure 1

Figure 1

Figure 2

Figure 2

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Comparison within groups

Patients with severe acne had the highest serum cathelicidin and lowest vitamin D levels, followed by patients with moderate acne, whereas those with mild acne had the lowest serum cathelicidin and highest vitamin D levels. However, the difference did not reach statistical significance (P=0.127 and 0.868, respectively) (Table 2). There was no significant difference between patients with mild, moderate, and severe acne as regards vitamin D status (P=0.950).

Table 2

Table 2

Patients with sufficient vitamin D levels had significantly lower serum cathelicidin levels than those with insufficient and deficient levels (P<0.001 for both). Similarly, controls with sufficient vitamin D levels had significantly lower serum cathelicidin levels than those with insufficient levels (P=0.018).

There was no significant difference between male and female patients and controls as regards serum cathelicidin, serum vitamin D, or vitamin D status (P=0.87, 0.978, and 0.771 for patients and 0.918, 0.967, and 0.881 for controls, respectively). Similarly, no statistically significant difference was detected between patients reporting adequate and those reporting inadequate sun exposure as regards the same parameters (P=0.248, 0.565, and 0.555, respectively). There was no significant difference between controls reporting adequate and those reporting inadequate sun exposure as regards serum cathelicidin or serum vitamin D (P=0.88 and 0.55, respectively). However, controls reporting adequate sun exposure had more sufficient vitamin D levels than those with inadequate sun exposure (P<0.001).

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Correlations

There was a highly significant negative correlation between serum vitamin D and serum cathelicidin in both patients and controls (r=−0.676, P<0.001; r=−0.609, P<0.001, respectively) (Figs 3 and 4). There was no significant correlation between age in either group and serum cathelicidin (r=0.158, P=0.228 and r=−0.111, P=0.56 for patients and controls, respectively) or serum vitamin D levels (r=−0.175, P=0.181 and r=0.24, P=0.065 for patients and controls, respectively). There was no significant correlation between duration of acne and serum cathelicidin (r=0.002, P=0.988) or serum vitamin D levels (r=−0.154, P=0.239).

Figure 3

Figure 3

Figure 4

Figure 4

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Receiver operating characteristics analysis

Receiver operating characteristic analysis was performed to calculate the cut-off value of serum cathelicidin associated with the occurrence of acne. The area under the curve was 0.866 (95% confidence interval was 0.790–0.942). The best cut-off value of serum cathelicidin for the occurrence of acne was 10.95 ng/ml, with a sensitivity of 81.7% and specificity of 86.7% (Fig. 5).

Figure 5

Figure 5

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Discussion

Acne vulgaris is a common multifactorial chronic inflammatory disease of the pilosebaceous unit. AMPs play a dual role in acne vulgaris: a protective role, by acting against P. acnes, or a proinflammatory role, by acting as signaling molecules 3. Cathelicidins are a family of small cationic AMPs with a wide range of immunomodulatory functions and antimicrobial activity. Expression of cathelicidin can be regulated by vitamin D and is enhanced under inflammatory conditions 5.

The present study revealed significantly high serum cathelicidin levels in acne patients as compared with controls, being highest in severe cases followed by moderate and mild cases. Our results are in agreement with a study conducted by Borovaya et al.17, which reported increased tissue expression of cathelicidin in acne patients returning to normal after 6 months of isotretinoin treatment.

However, it remains speculative whether the high serum cathelicidin levels in acne contribute to the disease pathogenesis, or merely represent a consequence to an inflammatory process or a defence mechanism against P. acnes. The production of cathelicidin in acne could be explained by several mechanisms. P. acnes releases various exogenous proteases, which, through the activation of the protease-activated receptor-2 on keratinocytes, can stimulate the production of inflammatory mediators, including cathelicidin, as well as IL-1α, IL-8, tumor necrosis factor-α, and various matrix metalloproteinases (MMP) 18. In addition, it has been reported that cathelicidin was detected in cultured human sebocytes, with higher expression levels following the addition of P. acnes culture supernatant 19.

Moreover, P. acnes is recognized by the innate immune system through TLR-2 2, leading to the induction of cytochrome p450 27B1 (CYP27B1), which converts 25(OH)D into the active form 1,25-dihydroxyvitamin D [1,25(OH)2D], resulting in gene transcription and increased expression of cathelicidin 11,12.

Cathelicidin could contribute to the pathogenesis of acne through several mechanisms. Cathelicidin could have a beneficial role in acne through limiting the growth of P. acnes19. In addition, several studies demonstrated the anti-inflammatory properties of cathelicidin, including the reduction of tumor necrosis factor-α production by macrophages stimulated by bacterial components 20,21 and the ability to neutralize lipopolysaccharides 22.

In contrast, cathelicidin could have harmful effects in acne. It triggers inflammatory cell recruitment (mast cells, monocytes, T lymphocytes, and neutrophils) through activating formyl peptide receptor-like 1 23,24. In addition, cathelicidin was reported to form complexes with self-DNA or self-RNA released from dead cells in systemic lupus erythematosus and psoriasis, which activate dendritic cells by triggering TLR-9 or TLR-7/8, respectively, leading to the production of proinflammatory cytokines and type-1 interferon 25–27.

Consequently, the finding of significantly elevated serum cathelicidin in our acne patients suggests that cathelicidin may play a role in the pathogenesis of acne. Henceforward, cathelicidin may represent a potential therapeutic target for the treatment of acne, and studies reported several drugs that inhibit cathelicidin expression, either directly or through its activating molecule kallikrein 5 (KLK5), which is a serine protease responsible for the cleavage and activation of cathelicidin into LL-37 28. Isotretinoin has been reported to normalize the increased cathelicidin expression in the skin of acne patients 17, a possible mechanism could be through decreasing the expression of TLR-2 on monocytes 29. In addition, anti-inflammatory doses of doxycycline have been demonstrated to decrease the expression of MMPs that proteolytically cleave KLK5 into its active form 30. Moreover, a study revealed that application of 15% azelaic acid gel twice daily in papulopustular rosacea decreased the expression of both cathelicidin and KLK5 31 and another pilot study demonstrated that topical application of epsilon-aminocaproic acid significantly reduced serine protease activity in rosacea patients after 12 weeks of treatment 32.

The present study revealed low serum vitamin D levels in acne patients in comparison with controls. However, the difference did not reach statistical significance. In addition, the levels were lowest in severe acne.

These results are in accordance with a study that reported that vitamin D deficiency significantly potentiates the inflammatory process in young men with severe acne 33. Moreover, animal studies suggest a therapeutic effect of vitamin D in acne through demonstrating comedolytic effects of vitamin D analogs on pseudocomedones in rhino mouse 34.

Further support is also shown by previous reports suggesting a possible beneficial role for vitamin D in acne. Sebocytes were demonstrated as vitamin D-responsive target cells 8, where binding of vitamin D to vitamin D receptors stimulates proliferation and inhibits differentiation as well as lipid synthesis by sebocytes 35. In addition, vitamin D decreased the production of inflammatory biomarkers, especially IL-6, IL-8, and MMP-9, by cultured sebocytes 36. Moreover, Zhang et al.37 demonstrated that vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting mitogen-activated protein kinase phosphatase-1.

Furthermore, vitamin D has an emerging role in regulating inflammation and chemokine production as well as antimicrobial and immunomodulatory actions 38. Vitamin D inhibits the proliferation of Th1 lymphocytes 39, which play a key role in the inflammation observed in acne 40. In addition, Agak et al.41 reported that IL-17 was induced by the action of P. acnes on peripheral blood mononuclear cells, an effect abolished by vitamin D.

Our study revealed that, despite lower levels of vitamin D, serum cathelicidin levels were significantly higher in acne patients compared with controls. In addition, there was a statistically significant negative correlation between serum vitamin D and cathelicidin levels in both patients and controls. Moreover, patients with sufficient vitamin D levels had significantly lower serum cathelicidin levels than those with insufficient and deficient levels, and controls with sufficient vitamin D levels had significantly lower serum cathelicidin levels than those with insufficient levels.

Therefore, although previous studies have shown the ability of vitamin D to induce cathelicidin 11,12, the present findings do not support the hypothesis of a direct relationship between vitamin D and cathelicidin level in acne patients and indicate that other factors might influence the expression levels of both molecules. The results of the present study suggest that cathelicidin and vitamin D may not only be working independently, but rather antagonistically in the pathogenesis of acne. These findings require further studies not only in acne vulgaris, but also other conditions in which these two molecules are playing a role.

In the same context, a study reported that a signaling lipid, sphingosine-1-phosphate, generated by sphingosine kinase 1, regulates cathelicidin expression through a nuclear factor-κβ-dependent pathway, independent of vitamin D receptor in epithelial cells 42.

Studies evaluating the relationship between vitamin D and cathelicidin have shown contradictory results, according to the different clinical settings. Recently, several authors reported that vitamin D supplementation increased the serum (or plasma) levels of both vitamin D and cathelicidin in Crohn’s disease patients, septic ICU patients, and athletes 43–45. Other studies reported a decrease in both levels with a positive correlation in critically ill ICU patients and HIV-1-infected patients 46,47.

In contrast, other studies revealed lower vitamin D levels and higher cathelicidin levels in patients with psoriasis, pulmonary tuberculosis, and congenital pneumonia 48–50. Moreover, a recent study reported decreased vitamin D and increased cathelicidin levels in acute asthma patients, with a negative correlation between the two 51.

Limitations to our study include the greater number of female patients compared with male patients. This could be attributed to female patients being more concerned with their beauty, and therefore more keen in seeking medical advice for acne. In addition, BMI was not measured, representing a limitation to our work. Another limitation is that cathelicidin levels were only measured in serum and not in tissue.

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Conclusion

The present study revealed significantly higher serum cathelicidin levels in acne patients than in controls, suggesting that cathelicidin may play a role in the pathogenesis of acne vulgaris, and consequently it may provide a possible therapeutic target for future treatment of acne vulgaris. In addition, lower (although nonsignificant) serum vitamin D levels were detected in acne patients, suggesting a possible role for vitamin D supplementation in acne treatment.

Further studies on larger number of patients and evaluating tissue cathelicidin levels in noninflammatory as well as inflammatory acne lesions are needed to shed more light on this topic. In addition, treatment of acne with topical vitamin D analogs, as well as vitamin D supplementation in acne patients with vitamin D deficiency would represent an attractive area of research.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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References

1. Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet 2012; 379:361–372.
2. Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, et al.. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 2002; 169:1535–1541.
3. Harder J, Tsuruta D, Murakami M, Kurokawa I. What is the role of antimicrobial peptides (AMP) in acne vulgaris? Exp Dermatol 2013; 22:386–391.
4. Doss M, White MR, Tecle T, Hartshorn KL. Human defensins and LL-37 in mucosal immunity. J Leukoc Biol 2010; 87:79–92.
5. Nijnik A, Hancock RE. The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr Opin Hematol 2009; 16:41–47.
6. Lai YH, Fang TC. The pleiotropic effect of vitamin D. ISRN Nephrol 2013; 2013:898125.
7. Chen TC, Chimeh F, Lu Z, Mathieu J, Person KS, Zhang A, et al.. Factors that influence the cutaneous synthesis and dietary sources of vitamin D. Arch Biochem Biophys 2007; 460:213–217.
8. Reichrath J. Vitamin D and the skin: an ancient friend, revisited. Exp Dermatol 2007; 16:618–625.
9. Youssef DA, Miller CW, El-Abbassi AM, Cutchins DC, Cutchins C, Grant WB, Peiris AN. Antimicrobial implications of vitamin D. Dermatoendocrinol 2011; 3:220–229.
10. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 2005; 19:1067–1077.
11. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al.. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311:1770–1773.
12. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al.. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173:2909–2912.
13. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004; 80 (Suppl):1678S–1688S.
14. Lehmann HP, Robinson KA, Andrews JS, Holloway V, Goodman SN. Acne therapy: a methodologic review. J Am Acad Dermatol 2002; 47:231–240.
15. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc 2010; 85:752–757. quiz 757–758.
16. Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 2009; 19:73–78.
17. Borovaya A, Dombrowski Y, Zwicker S, Olisova O, Ruzicka T, Wolf R, et al.. Isotretinoin therapy changes the expression of antimicrobial peptides in acne vulgaris. Arch Dermatol Res 2014; 306:689–700.
18. Lee SE, Kim JM, Jeong SK, Jeon JE, Yoon HJ, Jeong MK, Lee SH. Protease-activated receptor-2 mediates the expression of inflammatory cytokines, antimicrobial peptides, and matrix metalloproteinases in keratinocytes in response to Propionibacterium acnes. Arch Dermatol Res 2010; 302:745–756.
19. Lee DY, Yamasaki K, Rudsil J, Zouboulis CC, Park GT, Yang JM, Gallo RL. Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill Propionibacterium acnes. J Invest Dermatol 2008; 128:1863–1866.
20. Brown KL, Poon GF, Birkenhead D, Pena OM, Falsafi R, Dahlgren C, et al.. Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses. J Immunol 2011; 186:5497–5505.
21. Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol 2002; 169:3883–3891.
22. Scott A, Weldon S, Buchanan PJ, Schock B, Ernst RK, McAuley DF, et al.. Evaluation of the ability of LL-37 to neutralise LPS in vitro and ex vivo. PLoS One 2011; 6:e26525.
23. Yang D, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, et al.. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 2000; 192:1069–1074.
24. Niyonsaba F, Iwabuchi K, Someya A, Hirata M, Matsuda H, Ogawa H, Nagaoka I. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 2002; 106:20–26.
25. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, et al.. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 2011; 3:73ra19.
26. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al.. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007; 449:564–569.
27. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, et al.. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med 2009; 206:1983–1994.
28. Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, et al.. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 2007; 13:975–980.
29. Dispenza MC, Wolpert EB, Gilliland KL, Dai JP, Cong Z, Nelson AM, Thiboutot DM. Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients. J Invest Dermatol 2012; 132:2198–2205.
30. Kanada KN, Nakatsuji T, Gallo RL. Doxycycline indirectly inhibits proteolytic activation of tryptic kallikrein-related peptidases and activation of cathelicidin. J Invest Dermatol 2012; 132:1435–1442.
31. Coda AB, Hata T, Miller J, Audish D, Kotol P, Two A, et al.. Cathelicidin, kallikrein 5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel. J Am Acad Dermatol 2013; 69:570–577.
32. Two AM, Hata TR, Nakatsuji T, Coda AB, Kotol PF, Wu W, et al.. Reduction in serine protease activity correlates with improved rosacea severity in a small, randomized pilot study of a topical serine protease inhibitor. J Invest Dermatol 2014; 134:1143–1145.
33. Sinyavsky YA, Tsoy NO. Influence of nutritional patterns on the severity of acne in young adults. Vopr Pitan 2014; 83:41–47.
34. Nieves NJ, Ahrens JM, Plum LA, DeLuca HF, Clagett-Dame M. Identification of a unique subset of 2-methylene-19-nor analogs of vitamin D with comedolytic activity in the rhino mouse. J Invest Dermatol 2010; 130:2359–2367.
35. Clemens TL, Adams JS, Horiuchi N, Gilchrest BA, Cho H, Tsuchiya Y, et al.. Interaction of 1,25-dihydroxyvitamin-D3 with keratinocytes and fibroblasts from skin of normal subjects and a subject with vitamin-D-dependent rickets, type II: a model for study of the mode of action of 1,25-dihydroxyvitamin D3. J Clin Endocrinol Metab 1983; 56:824–830.
36. Lee WJ, Choi YH, Sohn MY, Lee SJ, Kim do W. Expression of inflammatory biomarkers from cultured sebocytes was influenced by treatment with vitamin D. Indian J Dermatol 2013; 58:327.
37. Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW, Goleva E. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 2012; 188:2127–2135.
38. Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med (Berl) 2010; 88:441–450.
39. Bikle DD. Vitamin D and the immune system: role in protection against bacterial infection. Curr Opin Nephrol Hypertens 2008; 17:348–352.
40. Mouser PE, Baker BS, Seaton ED, Chu AC. Propionibacterium acnes-reactive T helper-1 cells in the skin of patients with acne vulgaris. J Invest Dermatol 2003; 121:1226–1228.
41. Agak GW, Qin M, Nobe J, Kim MH, Krutzik SR, Tristan GR, et al.. Propionibacterium acnes induces an IL-17 response in acne vulgaris that is regulated by vitamin A and vitamin D. J Invest Dermatol 2014; 134:366–373.
42. Park K, Kim YI, Shin KO, Seo HS, Kim JY, Mann T, et al.. The dietary ingredient, genistein, stimulates cathelicidin antimicrobial peptide expression through a novel S1P-dependent mechanism. J Nutr Biochem 2014; 25:734–740.
43. Raftery T, Martineau AR, Greiller CL, Ghosh S, McNamara D, Bennett K, et al.. Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn’s disease: results from a randomised double-blind placebo-controlled study. United European Gastroenterol J 2015; 3:294–302.
44. Quraishi SA, De Pascale G, Needleman JS, Nakazawa H, Kaneki M, Bajwa EK, et al.. Effect of cholecalciferol supplementation on vitamin D status and cathelicidin levels in sepsis: a randomized, placebo-controlled trial. Crit Care Med 2015; 43:1928–1937.
45. He CS, Fraser WD, Tang J, Brown K, Renwick S, Rudland-Thomas J, et al.. The effect of 14 weeks of vitamin D3 supplementation on antimicrobial peptides and proteins in athletes. J Sports Sci 2016; 34:67–74.
46. Leaf DE, Croy HE, Abrahams SJ, Raed A, Waikar SS. Cathelicidin antimicrobial protein, vitamin D, and risk of death in critically ill patients. Crit Care 2015; 19:80.
47. Honda JR, Connick E, MaWhinney S, Chan ED, Flores SC. Plasma LL-37 correlates with vitamin D and is reduced in human immunodeficiency virus-1 infected individuals not receiving antiretroviral therapy. J Med Microbiol 2014; 63 (Pt 7):997–1003.
48. Al-Mutairi N, Shaaban D. Effect of narrowband ultraviolet B therapy on serum vitamin D and cathelicidin (LL-37) in patients with chronic plaque psoriasis. J Cutan Med Surg 2014; 18:43–48.
49. Zhan Y, Jiang L. Status of vitamin D, antimicrobial peptide cathelicidin and T helper-associated cytokines in patients with diabetes mellitus and pulmonary tuberculosis. Exp Ther Med 2015; 9:11–16.
50. Gad GI, Abushady NM, Fathi MS, Elsaadany W. Diagnostic value of anti-microbial peptide, cathelicidin in congenital pneumonia. J Matern Fetal Neonatal Med 2015; 28:2197–2200.
51. Arikoglu T, Kuyucu S, Karaismailoglu E, Batmaz SB, Balci S. The association of vitamin D, cathelicidin, and vitamin D binding protein with acute asthma attacks in children. Allergy Asthma Proc 2015; 36:51–58.
Keywords:

acne vulgaris; cathelicidin; vitamin D

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