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Last updated: 13th August 2010

Protease-activated receptor-2 mediates the expression of inflammatory cytokines, antimicrobial peptides, and matrix metalloproteinases in keratinocytes in response to Propionibacterium acnes.
Lee SE, Kim JM, Jeong SK, Jeon JE, Yoon HJ, Jeong MK, Lee SH
Department of Dermatology, Gangnam Severance Hospital, Yonsei University College of Medicine, 712 Eonjuro, Kangnam-gu, Seoul, 135-720, Korea.
Archives of dermatological research 2010 Aug
Propionibacterium acnes (P. acnes) has been known to produce various exogenous proteases, however, their role in acne pathogenesis remains largely unknown. Proteases elicit cellular responses, at least in part, via proteinase-activated receptor-2 (PAR-2), which is known to mediate inflammation and immune response. In this study, we investigated whether proteases from P. acnes could activate PAR-2 on keratinocytes and induce pro-inflammatory cytokines, antimicrobial peptides (AMPs), and matrix metalloproteinases (MMPs) via PAR-2 signaling. We examined PAR-2 expression and protease activity in acne lesions using immunofluorescence staining and in situ zymography. The effect of the culture supernatant of P. acnes on Ca(2+) signaling in immortalized keratinocytes (HaCaT) was measured using a fluorescence method. HaCaT cells were treated with P. acnes strain ATCC 6919 culture supernatant, with or without pretreatment with serine protease inhibitor or selective PAR-2 antagonist and the gene expression of pro-inflammatory cytokines, AMPs, and MMPs was detected using real-time reverse transcription-polymerase chain reaction. We found that the protease activity and PAR-2 expression were increased in acne lesions. The P. acnes culture supernatant induced calcium signaling in keratinocytes via PAR-2 and stimulated the mRNA expression of interleukin (IL)-1alpha, -8, tumor necrosis factor (TNF)-alpha, human beta defensin (hBD)-2, LL-37, MMP-1, -2, -3, -9, and -13 in keratinocytes, which was significantly inhibited by serine protease inhibitor as well as selective PAR-2 specific antagonist. These results indicate that PAR-2 plays an important role in the pathogenesis of acne by inducing inflammatory mediators in response to proteases secreted from P. acnes.
Mapping the Interactions between a Major Pollen Allergen and Human IgE Antibodies.
Ra´era G, Gadermaier G, de Paula V, Almeida MS, Egger M, Jahn-Schmid B, Almeida FC, Ferreira F, Valente AP
Centro Nacional de Ressonxxncia Magnética Nuclear, Universidade Federal do Rio de Janeiro, Instituto de Bioquímica Médica, Rio de Janeiro, Brazil.
Structure (London, England : 1993) 2010 Aug;18 (8):1011-1021
The interaction of specific IgE antibodies with allergens is a key event in the induction of allergic symptoms, thus representing an important target for therapeutic interventions in Type I allergies. We report here the solution NMR structure of Art v 1, the major mugwort pollen allergen. Art v 1 is the first protein structure with an allergenic defensin fold linked to a polyproline domain, which has not been identified in any reported allergen structure in the PDB. Moreover, the direct interaction of polyclonal IgE antibodies from an allergic patient has been mapped on the surface of an allergen for the first time. The data presented herein provide the basis for the design of tools for safe and effective vaccination against mugwort pollen allergy.
Intestinal Antimicrobial Gene Expression: Impact of Micronutrients in Malnourished Adults during a Randomized Trial.
Dhaliwal W, Shawa T, Khanam M, Jagatiya P, Simuyandi M, Ndulo N, Bevins CL, Sanderson IR, Kelly P
Institute of Cell and Molecular Science, Barts and The London School of Medicine, Queen Mary University of London, United Kingdom.
J Infect Dis. 2010 Sep 15;202(6):971-8.
BACKGROUND: Because both micronutrients and antimicrobial peptides protect against diarrhea, we looked for an effect on intestinal antimicrobial peptide gene expression during a randomized controlled trial of multiple micronutrient (MM) supplementation. METHODS: Consenting adults (n=287) in Lusaka, Zambia, were randomized to receive a daily MM supplement or placebo and were followed up for 3.3 years, with a crossover after 2 years. Intestinal biopsy samples were obtained at annual intervals, and messenger RNA of the intestinal antimicrobial peptides human alpha defensin (HD) 5, HD6, human beta-defensin (hBD) 1, hBD2, and LL-37 were quantified by real-time reverse-transcriptase polymerase chain reaction. Samples were also obtained during diarrhea episodes and after convalescence. RESULTS: There was no effect overall of treatment allocation. However, in malnourished adults (body mass index < or =18.5), HD5 mRNA was increased by 0.8 log transcripts/microg total RNA in MM recipients, compared with HD5 mRNA in placebo recipients (P=.007). During diarrhea, HD5 expression was reduced by 0.8 log transcripts in placebo recipients (P=.02) but was not reduced in MM recipients, nor was it reduced after the crossover. Correlations between HD5 and nutritional status were found that were sex-specific but not explained by serum leptin or adiponectin concentrations. CONCLUSIONS: Micronutrient supplementation was associated with up-regulation of HD5 only in malnourished adults. Interactions between antimicrobial gene expression and nutritional status may help to explain the increased risk of infection in individuals with malnutrition.
The epididymis-specific antimicrobial peptide beta-defensin 15 is required for sperm motility and male fertility in the rat (Rattus norvegicus).
Zhao Y, Diao H, Ni Z, Hu S, Yu H, Zhang Y
Shanghai Key Laboratory for Molecular Andrology, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
Cellular and molecular life sciences : CMLS 2010 Aug
Spermatozoa acquire forward motility and fertilizing capacity during their transit through the epididymis. The maturation process involves modifications of the sperm surface by different proteins that are secreted by a series of specialized regions in the epididymal epithelium. Here we show that the rat epididymis-specific beta-defensin 15 (Defb15) exhibits an androgen-dependent expression pattern, and it can bind to the acrosomal region of caput sperm. Coculture of caput spermatozoa with Defb15 antibody in vitro resulted in a significant decline in sperm motility. Moreover, the total and progressive motility of the spermatozoa dramatically decreased in rats when Defb15 was downregulated by lentivirus-mediated RNAi in vivo. Remarkably, knock down of Defb15 led to a reduction in fertility and embryonic development failure. In addition, the recombinant Defb15 showed antimicrobial activity in a dose-dependent fashion. These results suggest that Defb15 plays a dual role in both sperm maturation and pathogen defense in rat epididymis.
Paneth cells and innate mucosal immunity.
Ouellette AJ
Department of Pathology and Laboratory Medicine, Keck School of Medicine of The University of Southern California, Los Angeles, California, USA.
Current opinion in gastroenterology 2010 Aug
PURPOSE OF REVIEW: Recent evidence shows that disruption of Paneth cell homeostasis by induction of endoplasmic reticulum stress or autophagy, with consequent apoptosis, contributes to inflammation and morbidity in a variety of experimental mouse models. RECENT FINDINGS: Recent advances show that proinflammatory mediators in Paneth cell dense core secretory granules mediate tumor necrosis factor-alpha-induced shock, that Paneth cell alpha-defensins modulate the composition of the small intestinal microflora, that development of crypt organoid culture systems provides a novel means for investigating the crypt microenvironment, and that varied genetic defects that disrupt Paneth cell homeostasis are emergent as risk factors in inflammatory bowel disease. SUMMARY: This recent literature identifies Paneth cells as particularly sensitive targets of endoplasmic reticulum stress responses and implicates this unique small intestinal lineage in inflammatory bowel disease pathogenesis resulting from diverse heritable and environmental causes.
Synergistic effect of antibodies to human leukocyte antigens and defensins in pathogenesis of bronchiolitis obliterans syndrome after human lung transplantation.
Saini D, Angaswamy N, Tiriveedhi V, Fukami N, Ramachandran S, Hachem R, Trulock E, Meyers B, Patterson A, Mohanakumar T
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2010 Aug
BACKGROUND: This study aims to determine the role of antibodies to donor-mismatched human leukocyte antigen (HLA) developed during the post-transplant period in inducing defensins and their synergistic role in the pathogenesis of chronic rejection, bronchiolitis obliterans syndrome (BOS), after human lung transplantation (LTx). METHODS: Bronchoalveolar lavage (BAL) and serum from 21 BOS+ LTx patients were assayed for beta-defensins human neutrophil peptides (HNP) 1-3 (enzyme-linked immunosorbent assay [ELISA]) and anti-HLA antibodies (Luminex, Luminex Corp, Austin, TX). Human airway epithelial cells (AEC) were treated with anti-HLA antibodies, HNP-1/2, or both, and the levels of beta-defensin were measured by ELISA. Using a mouse model of obliterative airway disease induced by anti-major histocompatibility (MHC) class-I antibodies, we quantitatively and qualitatively determined neutrophil infiltration by myeloperoxidase (MPO) staining and activity by MPO assay, and defensin levels in the BAL. RESULTS: In human LTx patients, higher defensin levels correlated with presence of circulating anti-HLA antibodies (p < 0.05). AEC treated with anti-HLA antibodies or HNP-1/2, produced beta-defensin with synergistic effects in combination (612 +/- 06 vs 520 +/- 23 pg/ml anti-HLA antibody, or 590 +/- 10 pg/ml for HNP treatment; p < 0.05). Neutrophil numbers (6-fold) and activity (5.5-fold) were higher in the lungs of mice treated with anti-MHC antibodies vs control. A 2-fold increase in alpha-defensin and beta-defensin levels was also present in BAL on Day 5 after anti-MHC administrations. CONCLUSIONS: Anti-HLA antibodies developed during the post-transplant period and alpha-defensins stimulated beta-defensin production by epithelial cells, leading to increased cellular infiltration and inflammation. Chronic stimulation of epithelium by antibodies to MHC and resulting increased levels of defensins induce growth factor production and epithelial proliferation contributing to the development of chronic rejection after LTx.
Over-expression of paneth cell-derived anti-microbial peptides in the gut of patients with ankylosing spondylitis and subclinical intestinal inflammation.
Ciccia F, Bombardieri M, Ri´o A, Principato A, Giardina AR, Raiata F, Peralta S, Ferrante A, Drago S, Cottone M, Pitzalis C, Triolo G
Dipartimento Biomedico di Medicina Interna e Specialistica, Divisione di Reumatologia, Università di Palermo, Palermo, Italy, Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine, Unità Operativa di Anatomia Patologica, Azienda Ospedaliera Ospedali Riuniti Villa Sofia e Cervello, Palermo, Dipartimento Biomedico di Medicina Interna e Specialistica, Divisione di Gastroenterologia, Università di Palermo, Palermo, Bionat Italia and Dipartimento di Medicina, Pneumologia, Fisiologia e Nutrizione Umana, Azienda Ospedaliera Ospedali Riuniti Villa Sofia e Cervello, Palermo, Italy.
Rheumatology (Oxford, England) 2010 Aug
Objectives. Subclinical gut inflammation has been demonstrated in patients with AS. Altered expression of paneth cell (PC) anti-microbial peptides have been reported in the inflamed ileum of patients with Crohn´s disease (CD). Here, we investigated the expression of PC-derived peptides in subclinical gut inflammation in AS. Methods. Multiple adjacent mucosal biopsies from terminal ileum were obtained from 25 patients with AS, 30 CD and 15 healthy controls (HCs). Expression of human alpha-defensin 5 (HD-5), phospholipase A2 (PLA2), lysozyme and SOX-9 molecules was assessed by quantitative Taqman RT-PCR on mucosal samples. Immunohistochemistry with anti-human HD-5 antibody and genotyping of relevant NOD2 mutations was also performed. Results. HD-5, PLA2 and lysozyme transcript levels were strongly increased in AS and CD with similar degrees of intestinal inflammation when compared with normal controls. Immunohistochemical evaluation showed a normal number of PCs in both AS patients with chronic gut inflammation and CD patients with less-inflamed ileal samples. Conversely, CD patients with higher degree of gut inflammation had a reduced number of PCs and low expression levels of HD-5. Conclusion. In this study, we provide evidence that over-expression of PC-derived anti-microbial peptides occurs in the ileum of AS patients with subclinical gut inflammation, likely representing an important early alteration of the mucosal innate immune component and intestinal host defence in AS.
Antimicrobial Peptides and Peptaibols, Substitutes for Conventional Antibiotics.
Duclohier H
Institut de Physiologie et Biologie Cellulaires, UMR 6187 CNRS -Université de Poitiers, 1 rue Georges Bonnet , BP 633, 86022 Poitiers, France.
Current pharmaceutical design 2010 Aug
In this review, the antimicrobial properties of a number of peptides are described. We first deal with helical linear peptides such as the well-known gramicidin, magainins, melittin, and other less well-known or more recently discovered peptides. Then, beta-sheet peptides (defensins isolated from insects and also from mammalian tissues) and cyclic peptides like amphotericin B are described before the properties of peptaibols (containing the non-coded amino acid Aib) are discussed. Alamethicin remains the prototype of this class and its biophysical properties (mostly focussing on channel- or pore-formation in planar lipid bilayers) were and are still intensively studied. On the whole, we show how biophysical studies can explain the antimicrobial action of this ever expanding family of peptides.
Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum.
Biswas A, Liu YJ, Hao L, Mizoguchi A, Salzman NH, Bevins CL, Kobayashi KS
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14739-44.
Mutations in the NOD2 gene are strong genetic risk factors for ileal Crohn's disease. However, the mechanism by which these mutations predispose to intestinal inflammation remains a subject of controversy. We report that Nod2-deficient mice inoculated with Helicobacter hepaticus, an opportunistic pathogenic bacterium, developed granulomatous inflammation of the ileum, characterized by an increased expression of Th1-related genes and inflammatory cytokines. The Peyer's patches and mesenteric lymph nodes were markedly enlarged with expansion of IFN-gamma-producing CD4 and CD8 T cells. Rip2-deficient mice exhibited a similar phenotype, suggesting that Nod2 function likely depends on the Rip2 kinase in this model. Transferring wild-type bone marrow cells into irradiated Nod2-deficient mice did not rescue the phenotype. However, restoring crypt antimicrobial function of Nod2-deficient mice by transgenic expression of alpha-defensin in Paneth cells rescued the Th1 inflammatory phenotype. Therefore, through the regulation of intestinal microbes, Nod2 function in nonhematopoietic cells of the small intestinal crypts is critical for protecting mice from a Th1-driven granulomatous inflammation in the ileum. The model may provide insight into Nod2 function relevant to inflammation of ileal Crohn's disease.
Antimicrobial peptides expression by ocular surface cells in response to Acanthamoeba castellanii: an in vitro study.
Otri AM, Mohammed I, Abedin A, Cao Z, Hopkinson A, Panjwani N, Dua HS
University of Nottingham, Nottingham, UK.
The British journal of ophthalmology 2010 Aug
Aims Antimicrobial peptides (AMPs) are natural effectors of the innate immune response. Much work has been done to study their response and effects on bacterial and viral infection. Little if any information is available in relation to protozoal infections. The aim of the study was to comprehensively study the gene expression of the ocular AMPs in human corneal limbal epithelial cells stimulated with Acanthamoeba castellanii (AC). Methods Human corneal limbal epithelial cells were exposed to AC at different time points, up to 9 h, the genomic profile of the AMPs were analysed at these time point using real time PCR. corneal limbal epithelial cells not infected with AC were used as controls. Results Seven of the eight studied AMPs showed statistically significant upregulation in gene expression. Human beta Defensin 3 (hBD3) showed a very significant 10-fold upregulation in the exposed cells and Ribonuclease-7 (RNase-7) showed a very early and consistent increase. Human beta Defensin 1 (hBD1) was the only downregulated AMP. Conclusions The study data suggests a possible role of the AMPs in combating the amoebic infection at the ocular surface. Using AMPs singly or in combination is a promising avenue for further exploration in the treatment of the sight threatening Acanthamoeba keratitis.