In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

A deficiency in the expression of antimicrobial peptides may account for the susceptibility of patients with atopic dermatitis to skin infection with S. aureus.

It is well-recognized that young women with untreated premature ovarian failure (POF) are at increased risk of osteoporosis and bone fracture. Large, randomized trials have demonstrated that hormone replacement therapy with estrogen/progesterone in postmenopausal women can dramatically improve bone mineral density (BMD) and reduce fracture risk; however, there are little data on the effect of hormone replacement in young women with POF. At present, young women with POF are given either combined hormone replacement treatment or physiologic SSR (pSSR) consisting of combined transdermal estradiol and vaginal progesterone replacement regimens.This open-label, randomized controlled crossover pilot trial was designed to determine whether a regimen of pSSR could improve skeletal health among young women with POF caused by a variety of reasons. A total of 34 patients were randomized to receive a 4-week cycle of either pSSR (transdermal estradiol 100 g daily for week 1 and 150 g for weeks 2-4, with progesterone 200 mg twice daily for weeks 3-4) or standard hormone replacement therapy (sHRT) (oral ethinyl estradiol 30 g and norethisterone 1.5 mg daily for weeks 1-3, followed by 7 "pill-free" days for 12 months). Dual-energy x-ray absorptiometry was used to measure BMD at baseline and after each 12-month treatment period. During the study period, blood samples were collected for hormonal measurements and for markers of bone formation (bone alkaline phosphatase and procollagen type I aminoterminal propeptide) and bone resorption (CrossLaps [cross-linked C-terminal telopeptide of type I collagen]) before and after each washout period, and at 3, 6, and 12 months. Of the 34 women, 18 (mean age 27; range, 19-39 years) completed the study. LH (luteinizing hormone) and FSH (follicle-stimulating hormone) were decreased to a similar extent by both pSSR and sHRT. Treatment with pSSR increased the mean baseline lumbar spine BMD z-score by ϩ0.17 (95% confidence interval: ϩ0.07 to ϩ0.27; P ϭ 0.003), whereas there was no significant increase in response to sHRT (ϩ0.07, with a 95% confidence interval: Ϫ0.03 to ϩ0.18; P ϭ 0.2). During pSSR, the increment in lumbar spine BMD z-score was positively associated with estradiol (r ϭ ϩ0.49; P ϭ 0.04) and inversely associated with FSH (r ϭ Ϫ0.65; P ϭ 0.004). Both bone alkaline phosphatase and procollagen type I amino-terminal propeptide were increased significantly by pSSR ( ANOVA P Ͻ 0.001). In contrast, both of these bone formation markers were decreased by sHRT (P Ͻ 0.01). The bone resorption marker, CrossLaps, was suppressed by both regimens (P Ͻ 0.001). GYNECOLOGYVolume 66, Number 6 OBSTETRICAL AND GYNECOLOGICAL SURVEY

The microbiome can promote or disrupt human health by influencing both adaptive and innate immune functions. We tested whether bacteria that normally reside on human skin participate in host defense by killing Staphylococcus aureus, a pathogen commonly found in patients with atopic dermatitis (AD) and an important factor that exacerbates this disease. High-throughput screening for antimicrobial activity against S.aureus was performed on isolates of coagulase-negative Staphylococcus (CoNS) collected from the skin of healthy and AD subjects. CoNS strains with antimicrobial activity were common on the normal population but rare on AD subjects. A low frequency of strains with antimicrobial activity correlated with colonization by S.aureus. The antimicrobial activity was identified as previously unknown antimicrobial peptides (AMPs) produced by CoNS species including Staphylococcus epidermidis and Staphylococcus hominis. These AMPs were strain-specific, highly potent, selectively killed S.aureus, and synergized with the human AMP LL-37. Application of these CoNS strains to mice confirmed their defense function in vivo relative to application of nonactive strains. Strikingly, reintroduction of antimicrobial CoNS strains to human subjects with AD decreased colonization by S.aureus. These findings show how commensal skin bacteria protect against pathogens and demonstrate how dysbiosis of the skin microbiome can lead to disease.

Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. Here we report on our use of conditional gene targeting to examine the contribution of hypoxia-inducible factor 1, α subunit (HIF-1α) to myeloid cell innate immune function. HIF-1α was induced by bacterial infection, even under normoxia, and regulated the production of key immune effector molecules, including granule proteases, antimicrobial peptides, nitric oxide, and TNF-α. Mice lacking HIF-1α in their myeloid cell lineage showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. Conversely, activation of the HIF-1α pathway through deletion of von Hippel-Lindau tumor-suppressor protein or pharmacologic inducers supported myeloid cell production of defense factors and improved bactericidal capacity. HIF-1α control of myeloid cell activity in infected tissues could represent a novel therapeutic target for enhancing host defense.

Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.

Antimicrobial peptides and proteins (AMPs) are a diverse class of naturally occurring molecules that are produced as a first line of defense by all multicellular organisms. These proteins can have broad activity to directly kill bacteria, yeasts, fungi, viruses and even cancer cells. Insects and plants primarily deploy AMPs as an antibiotic to protect against potential pathogenic microbes, but microbes also produce AMPs to defend their environmental niche. In higher eukaryotic organisms, AMPs can also be referred to as 'host defense peptides', emphasizing their additional immunomodulatory activities. These activities are diverse, specific to the type of AMP, and include a variety of cytokine and growth factor-like effects that are relevant to normal immune homeostasis. In some instances, the inappropriate expression of AMPs can also induce autoimmune diseases, thus further highlighting the importance of understanding these molecules and their complex activities. This Primer will provide an update of our current understanding of AMPs.

Background-Atopic dermatitis (AD) is characterized by dry skin and a hyperreactive immune response to allergens, two cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJ) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway.