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Last updated: 13th August 2010

What is really in control of skin immunity: lymphocytes, dendritic cells, or keratinocytes? facts and controversies.
Rupec RA, Boneberger S, Ruzicka T
Department of Dermatology and Allergology, Ludwig-Maximilian-University, 80337 Munich, Germany.
Clin. Dermatol. ;28 (1):62-6
The pathophysiology of atopic dermatitis is still under discussion. Although it is widely accepted that environmental factors and a genetic predisposition are essential, the role of the innate and adaptive immune system and the functional cascade of the cells involved is still unclear. A concept that integrates all immune cells as equally essential has allure. In addition, barrier abnormalities due to mutations of the gene coding for filaggrin and down-regulation of antimicrobial peptides, such as LL-37 and beta-defensins 2 and 3, were very recently found to be relevant for the pathogenesis of atopic dermatitis.
Upregulation of defensins in burn sheep small intestine.
Poindexter BJ, Klein GL, Milner SM, Bick RJ
Department of Pathology and Laboratory Medicine, University of Texas Medical School, Houston.
Eplasty 2009 ;10 e6
Objective: The aim of this study was to visualize and localize the sheep antimicrobials, beta-defensins 1, 2, and 3, (SBD-1, SBD-2, SBD-3), sheep neutrophil defensin alpha (SNP-1), and the cathelicidin LL-37 in sheep small intestine after burn injury, our hypothesis being that these compounds would be upregulated in an effort to overcome a compromised endothelial lining. Response to burn injury includes the release of proinflammatory cytokines and systemic immune suppression that, if untreated, can progress to multiple organ failure and death, so protective mechanisms have to be initiated and implemented. Methods: Tissue sections were probed with antibodies to the antimicrobials and then visualized with fluorescently labeled secondary antibodies and subjected to fluorescence deconvolution microscopy and image reconstruction. Results: In both the sham and burn samples, all the aforementioned antimicrobials were seen in each of the layers of small intestine, the highest concentration being localized to the epithelium. SBD-2, SBD-3, and SNP-1 were upregulated in both enterocytes and Paneth cells, while SNP-1 and LL-37 showed increases in both the inner circular and outer longitudinal muscle layers of the muscularis externa following burn injury. Each of the defensins, except SBD-1, was also seen in between the muscle layers of the externa and while burn caused slight increases of SBD-2, SBD-3, and SNP-1 in this location, LL-37 content was significantly decreased. Conclusion: That while each of these human antimicrobials is present in multiple layers of sheep small intestine, SBD-2, SBD-3, SNP-1, and LL-37 are upregulated in the specific layers of the small intestine.
Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation.
Bauer JA, Chakravarthy AB, Rosenbluth JM, Mi D, Seeley EH, De Matos Granja-Ingram N, Olivares MG, Kelley MC, Mayer IA, Meszoely IM, Means-Powell JA, Johnson KN, Tsai CJ, Ayers GD, Sanders ME, Schneider RJ, Formenti SC, Caprioli RM, Pietenpol JA
Departments of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Clin. Cancer Res. 2010 Jan;16 (2):681-90
PURPOSE: To identify molecular markers of pathologic response to neoadjuvant paclitaxel/radiation treatment, protein and gene expression profiling were done on pretreatment biopsies. EXPERIMENTAL DESIGN: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel followed by concurrent paclitaxel/radiation. Tumor tissue from pretreatment biopsies was obtained from 19 of the 38 patients enrolled in the study. Protein and gene expression profiling were done on serial sections of the biopsies from patients that achieved a pathologic complete response (pCR) and compared to those with residual disease, non-pCR (NR). RESULTS: Proteomic and validation immunohistochemical analyses revealed that alpha-defensins (DEFA) were overexpressed in tumors from patients with a pCR. Gene expression analysis revealed that MAP2, a microtubule-associated protein, had significantly higher levels of expression in patients achieving a pCR. Elevation of MAP2 in breast cancer cell lines led to increased paclitaxel sensitivity. Furthermore, expression of genes that are associated with the basal-like, triple-negative phenotype were enriched in tumors from patients with a pCR. Analysis of a larger panel of tumors from patients receiving presurgical taxane-based treatment showed that DEFA and MAP2 expression as well as histologic features of inflammation were all statistically associated with response to therapy at the time of surgery. CONCLUSION: We show the utility of molecular profiling of pretreatment biopsies to discover markers of response. Our results suggest the potential use of immune signaling molecules such as DEFA as well as MAP2, a microtubule-associated protein, as tumor markers that associate with response to neoadjuvant taxane-based therapy.
Specific binding and chemotactic activity of mBD4 and its functional orthologue hBD2 to CCR6 expressing cells.
Roehrl J, Yang D, Oppenheim JJ, Hehlgans T
University of Regensburg, Germany;
J Biol Chem. 2010 Mar 5;285(10):7028-34.
Summary Beta-defensins are small antimicrobial polypeptides that are mainly expressed by epithelial cells and play an important role in the antimicrobial innate immune response. In addition to the direct microbicidal effects of these polypeptides members of the beta-defensin super family have the capacity to promote local innate inflammatory and systemic adaptive immune responses, which are in part mediated by the CC-chemokine receptor CCR6. Here we report the expression of recombinant mBD4 and its human orthologue hBD2 fused to the constant domain of human IgG1. Purified recombinant mBD4:Ig and hBD2:Ig fusion proteins retained potent antimicrobial activity. Furthermore, these beta-defensin fusion proteins showed specific binding to CCR6 expressing cells as revealed by flow cytometry. Interestingly, while hBD2:Ig bound to both human and mouse CCR6 expressing cells mBD4:Ig did only bind to mCCR6 expressing cells but not to hCCR6 expressing cells. The chemokine ligand CCL20 competed with the beta-defensin fusion proteins for specific binding to CCR6 as analyzed by FACS analysis. Both beta-defensin fusion proteins demonstrated chemotactic activity for cells expressing the mouse CCR6 receptor but mBD4:Ig did not induce chemotactic activity of cells expressing human CCR6. This result supports our finding that mBD4 does not interact with human CCR6 expressing cells. Further evidence for specific interaction of the beta-defensin fusion proteins with CCR6 expressing cells is demonstrated by the observation that CCL20 and beta-defensin fusion proteins desensitize each other in inducing chemotactic activity. In addition both mBD4:Ig and hBD2:Ig demonstrated CCR6-independent chemotaxis of freshly isolated mouse resident peritoneal cells and human PBMCs.
Vitamin D, innate immunity and upper respiratory tract infection.
Bartley J
Department of Otolaryngology-Head and Neck Surgery, Counties-Manukau District Health Board, Auckland, New Zealand.
The Journal of laryngology and otology 2010 Jan 1-5
Introduction:At the turn of the twentieth century, ultraviolet light was successfully used to treat tuberculosis of the skin. Upper respiratory tract infections had been inversely associated with sun exposure. During the last decade, basic scientific research demonstrated that vitamin D has an important anti-infective role.Method:Review of the relevant literature on the influence of vitamin D on innate immunity and respiratory tract infection.Results:Vitamin D is involved in the production of defensins and cathelicidin - antimicrobial peptides that provide a natural defence against potential microbiological pathogens. Vitamin D supplementation increases cathelicidin production. Low vitamin D levels are associated with an increased incidence of upper respiratory tract infections.Conclusions:Vitamin D appears to play an important role in the regulation of innate immunity in the upper respiratory tract. Optimal vitamin D levels and appropriate dosing schedules have yet to be determined.
Elevated expression of paneth cell CRS4C in ileitis-prone samp1/YitFc mice: Regional distribution, subcellular localization, and mechanism of action.
Shanahan MT, Vidrich A, Shirafuji Y, Dubois CL, Henschen-Edman A, Hagen SJ, Cohn SM, Ouellette AJ
University of California, Irvine, United States;
J Biol Chem. 2010 Mar 5;285(10):7493-504.
Paneth cells at the base of small intestinal crypts of Lieberkuhn secrete host defense peptides and proteins, including alpha-defensins, as mediators of innate immunity. Mouse Paneth cells also express alpha-defensin-related Defcr-rs genes that code for cysteine-rich sequence 4C (CRS4C) peptides that have a unique C-P-X triplet repeat motif. In ileitis-prone SAMP1/YitFc mice, Paneth cell levels of CRS4C mRNAs and peptides are induced more than a thousand fold relative to non-prone strains as early as 4 weeks of age, with the mRNA and peptide levels highest in distal ileum and below detection in duodenum. CRS4C-1 peptides are found exclusively in Paneth cells where they occur only in dense core granules, and thus are secreted to function in the intestinal lumen. CRS4C bactericidal peptide activity is membrane disruptive in that it permeabilizes E. coli and in-duces rapid microbial cell K+ efflux, but in a manner different from mouse alpha-defensin cryptdin-4. In in vitro studies, inactive pro-CRS4C-1 is converted to bactericidal CRS4C-1 peptide by matrix metalloproteinase-7 (MMP-7) proteolysis of the precursor proregion at the same residue positions that MMP-7 activates mouse pro-alpha-defensins. The absence of processed CRS4C in protein extracts of MMP-7-null mouse ileum demonstrates the in vivo requirement for intracellular MMP-7 in pro-CRS4C processing.
The innate immune molecule, NOD1, regulates direct killing of Helicobacter pylori by antimicrobial peptides.
Grubman A, Kaparakis M, Viala J, Allison C, Badea L, Karrar A, Boneca IG, Le Bourhis L, Reeve S, Smith IA, Hartland EL, Philpott DJ, Ferrero RL
Department of Microbiology, Monash University, Clayton, Victoria, Australia.
Cell Microbiol. 2010 May 1;12(5):626-39.
The cytosolic innate immune molecule, NOD1, recognizes peptidoglycan (PG) delivered to epithelial cells via the Helicobacter pylori cag pathogenicity island (cagPAI), and has been implicated in host defence against cagPAI(+)H. pylori bacteria. To further clarify the role of NOD1 in host defence, we investigated NOD1-dependent regulation of human beta-defensins (DEFBs) in two epithelial cell lines. Our findings identify that NOD1 activation, via either cagPAI(+) bacteria or internalized PG, was required for DEFB4 and DEFB103 expression in HEK293 cells. To investigate cell type-specific induction of DEFB4 and DEFB103, we generated stable NOD1´knockdown´ (KD) and control AGS cells. Reporter gene assay and RT-PCR analyses revealed that only DEFB4 was induced in an NOD1-/cagPAI-dependent fashion in AGS cells. Moreover, culture supernatants from AGS control, but not AGS NOD1 KD cells, stimulated with cagPAI(+)H. pylori, significantly reduced H. pylori bacterial numbers. siRNA studies confirmed that human beta-defensin 2 (hBD-2), but not hBD-3, contributes to the antimicrobial activity of AGS cell supernatants against H. pylori. This study demonstrates, for the first time, the involvement of NOD1 and hBD-2 in direct killing of H. pylori bacteria by epithelial cells and confirms the importance of NOD1 in host defence mechanisms against cagPAI(+)H. pylori infection.
The repertoire of equine intestinal alpha-defensins.
Bruhn O, Paul S, Tetens J, Thaller G
Institute of Animal Breeding and Husbandry, Christian-Albrechts-University of Kiel, Hermann-Rodewald-Strasse 6, D-24118 Kiel, Germany.
BMC Genomics 2009 ;10 631
BACKGROUND: Defensins represent an important class of antimicrobial peptides. These effector molecules of the innate immune system act as endogenous antibiotics to protect the organism against infections with pathogenic microorganisms. Mammalian defensins are classified into three distinct sub-families (alpha-, beta- and theta-defensins) according to their specific intramolecular disulfide-bond pattern. The peptides exhibit an antimicrobial activity against a broad spectrum of microorganisms including bacteria and fungi. Alpha-Defensins are primarily synthesised in neutrophils and intestinal Paneth cells. They play a role in the pathogenesis of intestinal diseases and may regulate the flora of the intestinal tract. An equine intestinal alpha-defensin (DEFA1), the first characterised in the Laurasiatheria, shows a broad antimicrobial spectrum against human and equine pathogens. Here we report a first investigation of the repertoire of equine intestinal alpha-defensins. The equine genome was screened for putative alpha-defensin genes by using known alpha-defensin sequences as matrices. Based on the obtained sequence information, a set of oligonucleotides specific to the alpha-defensin gene-family was designed. The products generated by reverse-transcriptase PCR with cDNA from the small intestine as template were sub-cloned and numerous clones were sequenced. RESULTS: Thirty-eight equine intestinal alpha-defensin transcripts were determined. After translation it became evident that at least 20 of them may code for functional peptides. Ten transcripts lacked matching genomic sequences and for 14 alpha-defensin genes apparently present in the genome no appropriate transcript could be verified. In other cases the same genomic exons were found in different transcripts. CONCLUSIONS: The large repertoire of equine alpha-defensins found in this study points to a particular importance of these peptides regarding animal health and protection from infectious diseases. Moreover, these findings make the horse an excellent species to study biological properties of alpha-defensins. Interestingly, the peptides were not found in other species of the Laurasiatheria to date. Comparison of the obtained transcripts with the genomic sequences in the current assembly of the horse (EquCab2.0) indicates that it is yet not complete and/or to some extent falsely assembled.
Antimicrobial Peptides Present in Mammalian Skin and Gut are Multifunctional Defence Molecules.
Metz-Boutigue MH, Shooshtarizadeh P, Prevost G, Haikel Y, Chich JF
Inserm 575, Physiopathologie due Systéme Nerveux, Université de Strasbourg, France.
Curr Pharm Des. 2010;16(9):1024-39.
Antimicrobial peptides are major components of the innate immune defence. They are well conserved along evolution, non-toxic and they ensure potent defences against a large number of pathogens. They act by direct killing of microorganisms and they possess additional roles in the regulation of adaptive immune responses, by recruting or stimulating immune cells. Skin and gut are positioned at the interface of internal milieu and external environment. They represent a physical and chemical barrier against pathogens invasion and the antimicrobial peptides limit pathogen growth in normal conditions. During infection or injury, some of these peptides are overexpressed and disrupt microbial membranes and/or stimulate immune cell recruitment, allowing to return to homeostasis or to increase inflammation. Antimicrobial peptides expression is altered in several diseases: alpha-defensins deficiency is related with Crohn´s disease and in skin, cathelicidin LL-37 and beta-defensin-2 are overexpressed in psoriasis, while in atopic dermatitis, their expression is decreased. The present review provides an up-to-date summary of the expression and the biological roles of the antimicrobial peptides found in the skin and gastrointestinal mucosa of the host, in normal and pathological conditions. The involvement of these natural antimicrobial peptides in inflammation, is also discussed.
A novel defensin-like peptide from salivary glands of the hard tick, Haemaphysalis longicornis.
Lu X, Che Q, Lv Y, Wang M, Lu Z, Feng F, Liu J, Yu H
Key Laboratory of Microbiological Engineering of Agricultural Environment, Life Sciences College of Nanjing Agricultural University, Ministry of Agriculture, Nanjing, Jiangsu, 210095 China.
Protein Sci. 2010 Mar;19(3):392-7.
A novel defensin-like antimicrobial peptide named longicornsin was isolated from the salivary glands of the hard tick, Haemaphysalis longicornis, using a 10-kDa cut-off Centriprep filter and reversed-phase high-performance liquid chromatography (RP-HPLC). Its amino acid sequence was determined as DFGCGQGMIFMCQRRCMRLYPGSTGFCRGFRCMCDTHIPLRPPFMVG by Edman degradation. The cDNA encoding longicornsin was cloned by cDNA library screening. The predicted protein from the cDNA sequence was composed of 78 amino acids including a mature longicornsin. It showed similarity with defensin-like peptides from other ticks by BLAST search. Different from most other tick defensin-like peptides, longicornsin had a C-terminal extension. Purified longicornsin exerted potent antimicrobial activities against bacteria and fungi. Interestingly, it even showed strong antimicrobial ability against drug-resistant microorganisms and Helicobacter pylori. The results of this study indicated that longicornsin is a potential candidate for novel antimicrobial drug design.