No abstract

SummaryMacrophages have been shown to kill Mycobacterium tuberculosis through the action of the antimicrobial peptide cathelicidin (CAMP), whose expression was shown to be induced by 1,25-dihydroxyvitamin D3 (1,25D3). Here, we investigated in detail the antimycobacterial effect of murine and human cathelicidin against Mycobacterium smegmatis and M. bovis BCG infections. Altogether, these data demonstrate that cathelicidin plays an important role in controlling intracellular survival of mycobacteria.

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 g/mouse), but not of its diluent, induced hypoferremia within 4 hours. To examine the chronic effects of hepcidin, we implanted either tumor xenografts engineered to overexpress human hepcidin or control tumor xenografts into nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Despite abundant dietary iron, mice with hepcidinproducing tumors developed more severe anemia, lower serum iron, and in- IntroductionAnemia of inflammation (AI), also referred to as anemia of chronic disease, is seen in a wide variety of inflammatory states including the acute systemic inflammatory response syndrome, chronic infections and inflammatory disorders, and some cancers. [1][2][3] AI is characterized by normocytic or microcytic iron-refractory anemia, low serum iron (hypoferremia), and relatively preserved bone marrow iron. 4 The pathogenic mechanisms that cause AI are not well understood but are thought to involve shortened erythrocyte lifespan with inadequate erythropoietic compensation due to the inhibitory effects of inflammatory cytokines on iron supply to the bone marrow, on erythropoietin production, and on the responsiveness of erythroid precursors to erythropoietin. 3,5 Recent studies in humans and mice suggest that the ironregulatory hormone hepcidin may be the principal mediator of AI. Hepcidin is an acute-phase peptide 6-8 whose overproduction leads to iron-limited erythropoiesis. Even without inflammation, transgenic mice overexpressing hepcidin suffered from severe ironrefractory anemia. 9 Patients with large hepatic adenomas that autonomously produce hepcidin developed hypoferremia and severe iron-refractory anemia, and the resection of the adenomas reversed the hematologic abnormalities. 10 The inflammatory stimuli lipopolysaccharide (LPS), Freund adjuvant, and turpentine increased the hepatic expression of mouse hepcidin-1. 8,[11][12][13] Within a few hours after the initiation of interleukin 6 (IL-6) infusion, human volunteers excreted increased amounts of urinary hepcidin and developed hypoferremia. 8 In humans, urinary hepcidin excretion was increased in AI. 7 In the aggregate, these studies suggest that AI may result from an inflammatory increase in hepcidin synthesis leading to hypoferremia and iron-refractory anemia.Although the hepcidin-1 transgenic mouse provides important insight into the actions of hepcidin, 9 it is not a suitable model for more detailed studies of the role of hepcidin in AI. The mice usually die at birth due to severe iron-deficiency anemia, presumably because hepcidin blocks placental iron transport, and the rare mosaic survivors require parenteral iron presumably because hepcidin overproduction blocks intestinal absorption of iron. Moreover, the existing models have emphasized the effects of hepcidin on iron absorption and have not specifically examined whether hepc...

The human cathelicidin, hCAP-18, is expressed both in neutrophils and in epithelial cells. hCAP-18 is processed to the antimicrobial peptide LL-37 by proteinase 3 in neutrophils. hCAP-18 is highly expressed in the epididymis with a subsequent high concentration in seminal plasma where the protein is present in its unprocessed and antimicrobially inactive form. We report here that hCAP-18 in seminal plasma is processed to generate a 38-amino acid antimicrobial peptide ALL-38 by the prostate-derived protease gastricsin when incubated at a pH corresponding to the vaginal pH. In accordance with this, seminal plasma derived hCAP-18 was found in its processed form in the vagina following sexual intercourse. The antimicrobial activity of ALL-38 against a variety of microorganisms tested is equal to that of LL-37. This enzymatic activation of a proantimicrobial substance in seminal plasma following exposure to the vaginal milieu represents a novel mechanism to prevent infection following sexual intercourse.Antimicrobial peptides are important effector molecules of the innate immune system from insects to humans (1, 2). The peptides are active against a broad spectrum of Gram-positive and Gram-negative bacteria as well as some fungi and enveloped viruses. These peptides may play a role in the regulation of the normal microflora (3). In mammals, the antimicrobial peptides are of major importance for the antimicrobial efficacy of professional phagocytes such as neutrophils and macrophages, but the peptides are also expressed in epithelial cells (4). In mammals, there are two large families of antimicrobial peptides, defensins and cathelicidins. Defensins are divided into the ␣-defensins found in neutrophils, macrophages, and Paneth cells in the small intestine, and the ␤-defensins, which are found widespread in epithelial cells. Cathelicidins are found mainly in neutrophils (5). Members of this protein family share a highly conserved N terminus of 12 kDa, named cathelin after a protein isolated from porcine neutrophils (6).Antimicrobial peptides are synthesized as preproproteins and (with the exception of defensins in neutrophils) stored as inactive proproteins (7). In order to become biologically active, the peptides must be liberated from the proproteins by proteolytic cleavage.The proteolytic generation of antimicrobial peptides is very important for the clearance of bacteria at sites of infection. In mice, ␣-defensins from Paneth cells in the small intestine are generated by matrilysin-mediated cleavage of prodefensins, and matrilysin knock-out mice have increased susceptibility to intestinal infections (8). Inhibition of activation of the porcine neutrophil cathelicidins by elastase impairs clearance of bacteria from wounds in vivo (9).The only human cathelicidin, hCAP-18, is a major protein of the specific granules of human neutrophils (10). It is processed to the antimicrobial peptide LL-37 by extracellular cleavage by proteinase 3 from azurophil granules following exocytosis (11). LL-37 has broad spectrum antimicro...