Decreased clearance of Pseudomonas aeruginosa from airways of mice deficient in lysozyme M.

Lysozyme is a ubiquitous and abundant, cationic, antimicrobial polypeptide of leukocytes and epithelia, but its biological function in host defense is largely unexplored. To ascertain the role of lysozyme during bacterial infection of murine airways, we exposed the airways of lysozyme M-deficient (lys M-/-) mice to the pulmonary pathogen Pseudomonas aeruginosa and examined the host's response to infection. Despite partial compensation as a result of the appearance of lysozyme P in the infected airways of lys M-/- mice, these lys M-/- mice showed decreased clearance of P.

The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study.

Hepcidin is the principal iron-regulatory hormone. It acts by binding to the iron exporter ferroportin, inducing its internalization and degradation, thereby blocking cellular iron efflux. The bioactive 25 amino acid (aa) peptide has a hairpin structure stabilized by 4 disulfide bonds.

Cellular iron: ferroportin is the only way out.

Ferroportin is the sole cellular efflux channel for iron and is regulated by the iron regulatory hormone hepcidin, which binds ferroportin and induces its internalization and degradation. New studies of ferroportin knockout mice define a key role for this transporter in physiological iron balance.

Distinct defensin profiles in Neisseria gonorrhoeae and Chlamydia trachomatis urethritis reveal novel epithelial cell-neutrophil interactions.

Defensins are key participants in mucosal innate defense. The varied antimicrobial activity and differential distribution of defensins at mucosal sites indicate that peptide repertoires are tailored to site-specific innate defense requirements. Nonetheless, few studies have investigated changes in peptide profiles and function after in vivo pathogen challenge.

Human defensin gene copy number polymorphisms: comprehensive analysis of independent variation in alpha- and beta-defensin regions at 8p22-p23.

To investigate defensin gene copy number polymorphisms, a quantitative real-time PCR assay was developed and used to study DNA from 27 unrelated individuals of diverse ethnic and racial backgrounds. The DEFB4 and DEFB103A genes varied in tandem, with copy numbers 2 to 8, with a mode of 6 per diploid genome (PDG). The combined copy numbers of the DEFA1 and DEFA3 genes ranged from 5 to 14, with a mode of 10 copies PDG.

Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin.

Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C, RgmC) are the major cause of juvenile hemochromatosis (JH). The protein product of HJV, hemojuvelin, contains a C-terminal glycosylphosphatidylinositol anchor, suggesting that it can be present in either a soluble or a cell-associated form. Patients with HJV hemochromatosis have low urinary levels of hepcidin, the principal iron-regulatory hormone secreted by the liver.

Primary iron overload with inappropriate hepcidin expression in V162del ferroportin disease.

Ferroportin disease (hemochromatosis type 4) is a recently recognized disorder of human iron metabolism, characterized by iron deposition in macrophages, including Kupffer cells. Mutations in the gene encoding ferroportin 1, a cellular iron exporter, are responsible for this iron storage disease, inherited as an autosomal dominant trait. We present clinical, histopathological, and radiological findings in a family with the most common ferroportin mutation, V162del.

The molecular basis of ferroportin-linked hemochromatosis.

Mutations in the iron exporter ferroportin (Fpn) (IREG1, SLC40A1, and MTP1) result in hemochromatosis type IV, a disorder with a dominant genetic pattern of inheritance and heterogeneous clinical presentation. Most patients develop iron loading of Kupffer cells with relatively low saturation of plasma transferrin, but others present with high transferrin saturation and iron-loaded hepatocytes. We show that known human mutations introduced into mouse Fpn-GFP generate proteins that either are defective in cell surface localization or have a decreased ability to be internalized and degraded in response to hepcidin.

Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs.

Hepcidin is the principal iron regulatory hormone and its overproduction contributes to anemia of inflammation (AI). In vitro, hepcidin binds to and induces the degradation of the exclusive iron exporter ferroportin. We explored the effects and distribution of synthetic hepcidin in the mouse.

Defensins and other antimicrobial peptides: a historical perspective and an update.

Antimicrobial peptides are effectors of innate immunity in phagocytes, body fluids and epithelia. In mammals, defensins, peptides with a characteristic six-cysteine framework, are particularly abundant and widely distributed in various animal species and tissues. The first part of this review provides a historical overview of the ideas that led to the current state-of-the-art in antimicrobial peptides, and the second part is an update on mammalian defensins and their role in host defense to infections.

TGF-alpha regulates TLR expression and function on epidermal keratinocytes.

The expression of TLRs on epithelial cells provides a first line of defense against invading pathogens. We investigated the regulated expression and function of TLR5 and TLR9 on human keratinocytes, because we found by immunohistochemistry that these TLRs are expressed in distinct layers of the epidermis. We found that TGF-alpha, a growth and differentiation factor that is present during wound healing and in psoriasis, increased the expression of both TLR5 and TLR9 on keratinocytes.

Differential regulation of beta-defensin expression in human skin by microbial stimuli.

In response to infection, epithelia mount an innate immune response that includes the production of antimicrobial peptides. However, the pathways that connect infection and inflammation with the induction of antimicrobial peptides in epithelia are not understood. We analyzed the molecular links between infection and the expression of three antimicrobial peptides of the beta-defensin family, human beta-defensin (hBD)-1, hBD-2, and hBD-3 in the human epidermis.

Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function.

Hepcidin, a key regulator of iron metabolism, is synthesized by the liver. Hepcidin binds to the iron exporter ferroportin to regulate the release of iron into plasma from macrophages, hepatocytes, and enterocytes. We analyzed liver samples from patients undergoing hepatic surgery for cancer or receiving liver transplants and analyzed correlations between clinical parameters and liver hepcidin mRNA and urinary hepcidin concentrations.

Hepcidin--a regulator of intestinal iron absorption and iron recycling by macrophages.

Hepcidin is a recently discovered peptide made in the liver, distributed in plasma and excreted in urine. This peptide hormone is the homeostatic regulator of intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores. Hepcidin acts by inhibiting the efflux of iron through ferroportin, the sole known iron exporter of enterocytes, macrophages and hepatocytes.

Hepcidin in iron overload disorders.

Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload.

Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.

Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells.

Increased bronchoalveolar lavage human beta-defensin type 2 in bronchiolitis obliterans syndrome after lung transplantation.

Human beta-defensin-2 (HBD)2 is an antimicrobial peptide that participates in the innate host immune defense. HBD2 is present in bronchoalveolar lavage (BAL) fluid during conditions associated with airway inflammation but not in normal subjects. We measured HBD2 concentrations by semiquantitative Western analysis in BAL of prelung transplant patients (PRE) and postlung-transplant BAL associated with either "quiescent" histopathology (i.

Hepcidin is decreased in TFR2 hemochromatosis.

The hepatic peptide hepcidin is the key regulator of iron metabolism in mammals. Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Juvenile hemochromatosis is associated with hepcidin or hemojuvelin mutations, and these patients have low or absent urinary hepcidin.

Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia.

The iron-regulatory hormone hepcidin has been proposed as the mediator of anemia of inflammation (AI). We examined the acute and chronic effects of hepcidin in the mouse. Injections of human hepcidin (50 microg/mouse), but not of its diluent, induced hypoferremia within 4 hours.

Lysozyme levels in the nasal secretions of patients with perennial allergic rhinitis and recurrent sinusitis.

Background: The association of perennial allergic rhinitis (PAR) with recurrent sinusitis (RS) is well recognized. Anatomic abnormalities at the osteomeatal complex or ciliary dysfunction may play a significant role in some patients. However, for most patients with allergy, the determinants of RS are unknown.

Defensins: antimicrobial peptides of vertebrates.

This review, based on my presentation at the French Academy of Sciences on May 19, 2003, describes recent progress in the study of antimicrobial peptides, mediators of innate immunity in plants and animals. The main focus is on vertebrate defensins, a family of cysteine-rich antimicrobial peptides abundantly represented in human cells and tissues.

Hepcidin in iron metabolism.

Purpose Of Review: Hepcidin is a recently discovered hepatic peptide that regulates intestinal iron absorption as well as maternal-fetal iron transport across the placenta. It probably also affects the release of iron from hepatic stores and from macrophages involved in the recycling of iron from hemoglobin. Connecting iron metabolism to innate immunity, hepcidin is a key mediator of hypoferremia of inflammation.

Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'-UTR of the HAMP gene.

Juvenile hereditary hemochromatosis is a genetically heterogeneous disorder transmitted as an autosomal recessive trait. It is most often caused by mutations in the HJV gene and rarely in the HAMP gene. Hepcidin is considered to constitute a negative regulator of iron absorption, and its production is increased in inflammatory states and iron overload.