cholecalciferol and Bacterial-Infections

As traditional antibiotics gradually become inefficient, there is a high demand for development of anti-infectives with a mechanism of action that is different from existing antibiotics. Current antibiotics target the pathogen directly, thereby contributing to the selection of multidrug-resistant bacterial strains. AMPs, such as the human cathelicidin LL-37, are small cationic peptides that are part of host defense. They eliminate microbes through diverse mechanisms, thereby contributing to resolution of infections and maintenance of epithelial barrier function. The multiplicity of these mechanisms of action might be a key to restrict the development of resistant bacterial strains. The discovery of LL-37-inducing components, such as butyrate and vitamin D(3), has opened new avenues to prevent or treat infections. Butyrate and vitamin D(3) are potent inducers of LL-37 but in addition, have many other effects on host immunity. Here, we summarize current data on the effects that LL-37 and its inducers display on the innate immune response and discuss the feasibility for development of these inducers as possible drugs to prevent or treat infections.

Topics: Antimicrobial Cationic Peptides; Bacterial Infections; Bronchi; Butyrates; Cathelicidins; Cholecalciferol; Colon; Humans; Immunity, Innate; Neutrophils; Skin

Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.

Topics: Antigen Presentation; Autoimmune Diseases; Bacterial Infections; Blood Bactericidal Activity; Cathelicidins; Cholecalciferol; Gene Expression Regulation; Humans; Immunomodulation; Inflammation; Signal Transduction; Skin

There is a recent renewed interest in vitamin D metabolism and pathophysiology, due to its recent description as a hormone with a positive impact on global health rather than a strictly bone hormone: vitamin D could be a protective factor against infection, autoimmunity, cardiovascular morbidity, and cancer. By contrast, vitamin D deficiency appears to be increasingly frequent worldwide. We propose a review of these new aspects of vitamin D metabolism, with a focus on vitamin D status in a local pediatric cohort. There is an urgent need for revisiting current guidelines on vitamin D supplementation and for closely monitoring serum vitamin D in children with chronic diseases, i.e., at greater risk of cardiovascular impairment, bone morbidity, infectious disease, and acute inflammation.

Topics: Autoimmune Diseases; Bacterial Infections; Bone and Bones; Bone Density Conservation Agents; Bone Diseases; Cardiovascular Diseases; Child; Cholecalciferol; Evidence-Based Medicine; France; Global Health; Humans; Inflammation; Meta-Analysis as Topic; Neoplasms; Prevalence; Risk Factors; Virus Diseases; Vitamin D; Vitamin D Deficiency

Topics: Agammaglobulinemia; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacterial Infections; Calcium; Cholecalciferol; Electrolytes; Female; Humans; Hypocalcemia; Hypokalemia; Hypoparathyroidism; Hypophosphatemia; Immunoglobulins, Intravenous; Immunologic Deficiency Syndromes; Magnesium; Middle Aged; Thymoma; Weight Loss

Immune defence against microbes depends in part on the production of antimicrobial peptides, a process that occurs in a variety of cell types but is incompletely understood. In this study, the mechanisms responsible for the induction of cathelicidin and beta-defensin antimicrobial peptides were found to be independent and specific to the cell type and stimulus. Vitamin D3 induced cathelicidin expression in keratinocytes and monocytes but not in colonic epithelial cells. Conversely, butyrate induced cathelicidin in colonic epithelia but not in keratinocytes or monocytes. Distinct factors induced beta-defensin expression. In all cell types, vitamin D3 activated the cathelicidin promoter and was dependent on a functional vitamin D responsive element. However, in colonic epithelia butyrate induced cathelicidin expression without increasing promoter activity and vitamin D3 activated the cathelicidin promoter without a subsequent increase in transcript accumulation. Induction of cathelicidin transcript correlated with increased processed mature peptide and enhanced antimicrobial activity against Staphylococcus aureus. However, induction of beta-defensin-2 expression did not alter the innate antimicrobial capacity of cells in culture. These data suggest that antimicrobial peptide expression is regulated in a tissue-specific manner at transcriptional, post-transcriptional and post-translational levels. Furthermore, these data show for the first time that innate antimicrobial activity can be triggered independently of the release of other pro-inflammatory molecules, and suggest strategies for augmenting innate immune defence without increasing inflammation.

Topics: Antimicrobial Cationic Peptides; Bacterial Infections; beta-Defensins; Blotting, Western; Butyrates; Cathelicidins; Cells, Cultured; Cholecalciferol; Colitis; Epithelial Cells; Gene Expression Regulation; Humans; Immunity, Innate; Immunohistochemistry; Keratinocytes; Monocytes; Mutagenesis, Site-Directed; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Skin Diseases, Bacterial; Transfection