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      LL-37 but Not 25-Hydroxy-Vitamin D Serum Level Correlates with Healing of Venous Leg Ulcers

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          Abstract

          Human cathelicidin, LL-37, is small antimicrobial peptide, which reveals also some immunomodulatory and proangiogenic properties and, therefore, may promote wound healing. The expression of LL-37 is controlled by various factors, including vitamin D. Thus, any disturbances in vitamin D level may influence LL-37 production and, possibly, affect wound healing. Since deficiency of vitamin D was identified as a common problem in the population, this proof of concept study aimed to verify the relationship between serum levels of LL-37, vitamin D, and healing rate of venous leg ulcers. The study involved small group ( n = 19) of patients with venous leg ulcers. Apart from non-venous ulcer aethiology, compression intolerance, active vein thrombosis, and wound infection, the exclusion criteria concerned also kidney insufficiency. The results of the analysis of wound healing rates were correlated with patients’ serum levels of 25(OH) vitamin D and LL-37. In addition, serum levels of pro-inflammatory cytokines (IL-6, IL-8, and TNF) were analyzed. We have found strong association between serum concentrations of LL-37 and the healing rates in patients with leg ulcers. Despite the fact that 25(OH) vitamin D levels in all patients were below the normal range, they did not show any correlation with healing rates. Furthermore, no association was observed between serum levels of 25(OH) vitamin D and LL-37. No significant correlation between tested pro-inflammatory cytokines and healing rate, LL-37, or 25(OH) vitamin D levels was also observed. Regardless of small study group, our results suggest that the assessment of serum concentration of LL-37, but not 25-hydroxy vitamin D, may help in predicting the wound healing efficacy. Moreover, this assessment may be useful in pre-selection of patients, which could benefit from local treatment with exogenous LL-37.

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          Antiviral Activity and Increased Host Defense against Influenza Infection Elicited by the Human Cathelicidin LL-37

          The extensive world-wide morbidity and mortality caused by influenza A viruses highlights the need for new insights into the host immune response and novel treatment approaches. Cationic Host Defense Peptides (CHDP, also known as antimicrobial peptides), which include cathelicidins and defensins, are key components of the innate immune system that are upregulated during infection and inflammation. Cathelicidins have immunomodulatory and anti-viral effects, but their impact on influenza virus infection has not been previously assessed. We therefore evaluated the effect of cathelicidin peptides on disease caused by influenza A virus in mice. The human cathelicidin, LL-37, and the murine cathelicidin, mCRAMP, demonstrated significant anti-viral activity in vivo, reducing disease severity and viral replication in infected mice to a similar extent as the well-characterized influenza virus-specific antiviral drug zanamivir. In vitro and in vivo experiments suggested that the peptides may act directly on the influenza virion rather than via receptor-based mechanisms. Influenza virus-infected mice treated with LL-37 had lower concentrations of pro-inflammatory cytokines in the lung than did infected animals that had not been treated with cathelicidin peptides. These data suggest that treatment of influenza-infected individuals with cathelicidin-derived therapeutics, or modulation of endogenous cathelicidin production may provide significant protection against disease.
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            The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium.

            The human cathelicidin anti-microbial protein, hCAP18 is a component of the innate immune system and has broad anti-microbial activity conferred by its C-terminal fragment LL-37. hCAP18 is constitutively produced in leukocytes and is induced in barrier organs upon inflammation and infection. We demonstrate here a novel role for this peptide in re-epithelialization of skin wounds. We show that high levels of hCAP18 are produced in skin in vivo upon wounding. The highest hCAP18 levels are attained at 48 h post-injury, declining to pre-injury levels upon wound closure. hCAP18 is detected in the inflammatory infiltrate and in the epithelium migrating over the wound bed. In chronic ulcers, however, hCAP18 levels are low and immunoreactivity for hCAP18/LL-37 is absent in ulcer edge epithelium. Using a noninflammatory ex vivo wound healing model, composed of organ-cultured human skin, we show that hCAP18 is strongly expressed in healing skin epithelium, and that treatment with antibodies raised and affinity purified against LL-37, inhibits re-epithelialization in a concentration-dependent manner. Immunoreactivity for the proliferation marker Ki67 is absent in the epithelium of such inhibited wounds, suggesting that LL-37 may play a part in epithelial cell proliferation. Thus, we suggest that, in addition to being an anti-microbial peptide, LL-37 also plays a part in wound closure and that its reduction in chronic wounds impairs re-epithelialization and may contribute to their failure to heal.
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              Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa.

              Vitamin D deficiency is associated with susceptibility to tuberculosis (TB) in HIV-uninfected people in Europe, but it is not known whether such an association exists among HIV-infected people in subtropical Africa. We conducted a cross-sectional study to determine whether vitamin D deficiency was associated with susceptibility to active TB in HIV-uninfected (n = 196) and HIV-infected (n = 174) black Africans in Cape Town, South Africa. We also investigated whether there was evidence of seasonal variation in vitamin D status and TB notifications in this setting over an 8-y period. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) was present in 232 (62.7%) of 370 participants and was associated with active TB in both HIV-uninfected (odds ratio = 5.2, 95% confidence interval: 2.8-9.7; P < 0.001) and HIV-infected (odds ratio = 5.6, 95% confidence interval: 2.7-11.6; P < 0.001) people. Vitamin D status varied according to season: The mean serum 25(OH)D concentration was highest in January through March and lowest in July through September (56.8 vs. 30.7 nmol/L, respectively; P < 0.001). Reciprocal seasonal variation in TB notifications was observed: The mean number of TB notifications per quarter for Cape Town in 2003 to 2010 was lowest in April through June and highest in October through December (4,222 vs. 5,080; P < 0.001). Vitamin D deficiency is highly prevalent among black Africans in Cape Town and is associated with susceptibility to active TB both in the presence and absence of HIV infection. Reciprocal seasonal variation in serum 25(OH)D concentration and TB notifications suggests that seasonal variations in vitamin D status and TB incidence in this setting are causally related.
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                Author and article information

                Contributors
                tomekgrzela@gmail.com
                Journal
                Arch Immunol Ther Exp (Warsz)
                Arch. Immunol. Ther. Exp. (Warsz.)
                Archivum Immunologiae et Therapiae Experimentalis
                Springer International Publishing (Cham )
                0004-069X
                1661-4917
                23 September 2016
                23 September 2016
                2017
                : 65
                : 5
                : 455-461
                Affiliations
                [1 ]ISNI 0000000113287408, GRID grid.13339.3b, Laboratory of Cell Molecular Biology, Department of Histology and Embryology, Biostructure Research Centre, , Medical University of Warsaw, ; Chalubinskiego 5, 02-004 Warsaw, Poland
                [2 ]ISNI 0000000113287408, GRID grid.13339.3b, Postgraduate School of Molecular Medicine, , Medical University of Warsaw, ; Warsaw, Poland
                [3 ]ISNI 0000000113287408, GRID grid.13339.3b, Department of Otolaryngology, , Medical University of Warsaw, ; Warsaw, Poland
                [4 ]Clinic of Phlebology, Warsaw, Poland
                Article
                423
                10.1007/s00005-016-0423-9
                5602047
                27663530
                9718eee5-5ed8-4148-9b97-4f81442f6d82
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 1 January 2016
                : 10 June 2016
                Funding
                Funded by: Medical University of Warsaw
                Award ID: 1M15/NM2/15
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017

                Immunology
                cathelicidin,healing rate,ll-37,venous leg ulcer,vitamin d
                Immunology
                cathelicidin, healing rate, ll-37, venous leg ulcer, vitamin d

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