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PubMed1988

Phagocyte function in reactive arthritis.

The pathogenesis of reactive arthritis is multifactorial. The possible pathogenetic mechanisms include the role of microbial antigens which cross-react with the host tissue or trigger cytotoxic immune response. In addition an exaggerated inflammatory response of the host may contribute to the clinical picture of the acute arthritis and its late sequels. In this review, we present data showing that HLA-B27 positive subjects show enhanced neutrophil (PMN) migration and their sera support PMN migration more than HLA-B27 negative sera. Enhanced PMN function is persistent in patients with previous severe reactive arthritis or with late inflammatory sequels. In addition to hyperreactive PMNs, monocytes from patients with previous yersinia arthritis, but also from healthy HLA-B27 positive subjects, respond to stimulation with lipopolysaccharide by enhanced production of inflammatory monokines compared with HLA-B27 negative healthy controls. Thus, hyperreactive phagocytes can contribute to the severe inflammatory complications seen in patients with reactive arthritis. The primed phagocytes can also respond vigorously when stimulated either with endogenous mediators of inflammation or with endotoxin released during a new infection or as a sequel of change in the mucosal permeability described in patients with spondyloarthropathy.

Arthritis, Infectious↗
PubMed1997

Effects of sanguinarium, chlorhexidine and tetracycline on neutrophil viability and functions in vitro.

The effectiveness of an ideal antimicrobial agent depends on its ability to kill microbes with minimal toxicity to host cells. Depending on the treatment regimen, antimicrobial agents come into contact with host cells for various intervals of time. Sanguinarium (SANG), chlorhexidine (CHX) and tetracycline (TET) are 3 antimicrobial agents frequently used in the management of periodontal infections. However, their effects on host immune cells during different treatment regimens are not known. Due to their ability to serve as the first line of host defense against microbial infections, we have compared the effects of these antimicrobial agents on human neutrophil functions and viability. The results show that SANG is not lytic to neutrophils from peripheral blood or crevicular fluid, at all concentrations tested. However, exposures of neutrophils to very low concentrations of SANG (0.001%) inhibits neutrophil chemotaxis, oxidative metabolism and degranulation within 5 min. Increasing the exposure time results in a similar inhibition of neutrophil functions, albeit at 50-100 fold lower concentrations of SANG. CHX rapidly disrupts the cell membrane of both crevicular and peripheral blood neutrophils at concentrations above 0.005% within 5 min, and inhibition of all neutrophil functions is due to its lytic properties. While TET is least toxic to neutrophils, a dose dependent inhibition of neutrophil functions is dependent on the calcium concentrations of the cellular environment, and is observed only above 0.04% or higher concentrations in the absence of calcium. The data suggest that a critical cumulative concentration of these drugs is essential for their toxicity and inhibition of neutrophil functions. Therefore, both the length of exposure and the dose of the drug both are critical while considering the effectiveness of SANG, CHX or TET in the treatment of infections. Furthermore, due to differences in their mechanisms of action, the consequences of their effects on neutrophils may have significant bearing on tissue pathology as well as on their therapeutic efficacy.

Adult↗
PubMed2026

Adaptive Evolution Reveals Metabolic Plasticity and Functional Redundancy in an Anaerobic Microbiome under Extreme Ammonia Stress.

Ammonia toxicity represents a primary biochemical bottleneck governing microbial community structure and performance during the anaerobic digestion of the organic fraction of municipal solid waste. However, the mechanistic basis of microbial adaptation to chronic ammonia levels remains poorly characterized. In this study, a long-term sequential enrichment strategy under progressively increasing ammonia concentrations (350-1500 mgN L-1), integrated with genome-centric metagenomics and metatranscriptomics, was employed to resolve the response of an organic waste-degrading microbiome over a 240 day period. Increasing ammonia pressure induced a progressive decline in methanogenesis and accumulation of volatile fatty acids, particularly acetate. Despite these inhibitory pressures, methane production was only halved relative to the initial baseline reflecting a resilient methanogenic community. This stability was driven by a restructuring of the microbiome, where functional redundancy across divergent taxa preserved core metabolic functions. Key adaptive responses included the reconfiguration of carbon fixation pathways, specifically via a variant of the Wood-Ljungdahl pathway coupled with the glycine cleavage system acting as an alternative acetate oxidation route, as well as sustained osmoprotectant biosynthesis. Cellular homeostasis was preserved through H+ replenishment via multiple energy-converting complexes and K+ influx to maintain cation-proton balance. Collectively, these findings demonstrate that metabolic plasticity and the preservation of core metabolic functions are the primary determinants of ammonia resilience, sustaining methane production under inhibitory conditions.

Ammonia↗
PubMed2001

Changes in bacterial concentration in the liver correlate with that in the hepaticojejunostomy after bile duct reconstruction: implication in the pathogenesis of postoperative cholangitis.

Postoperative cholangitis is a frequent and unpredictable complication of unknown etiology following bile duct reconstruction (BDR), particularly for biliary atresia. This study was undertaken to correlate the growth of bacteria in the hepaticojejunostomy with that in the liver after BDR. Quantitative bacterial culture was done on the specimens taken from the liver and from the hepaticojejunostomy at 1 week (group 1, n = 7), 1 month (group 2, n = 7), and 2 months (group 3, n = 7) following BDR with Roux-en-Y hepaticojejunostomy in piglets after 2 weeks of common bile duct ligation. The histological examination of the liver and the hepaticojejunostomy, as well as serial monitoring of hemogram and liver function tests, were performed to correlate the findings with the bacterial concentration of the liver and the hepaticojejunostomy following BDR. The bacterial concentration of the hepaticojejunostomy, expressed as log10 colony-forming units per gram (log10 CFU/g) of the hepaticojejunostomy, showed a progressive decrease from 8.38 +/- 1.36 in group 1, 7.07 +/- 2.54 in group 2, to 3.56 +/- 1.31 in group 3 (p = 0.001). The log10 CFU/g of the liver also showed a progressive decrease from 5.02 +/- 1.59 in group 1, 3.16 +/- 1.56 in group 2, to 2.19 +/- 1.09 in group 3 (p = 0.006). There was a significant positive correlation of the log10 CFU/g of the liver (n = 21) with that of the hepaticojejunostomy (n = 21) following BDR (r = 0.600, p = 0.004). Most of the infectious pathogens isolated from the liver were also isolated from the hepaticojejunostomy. The changes in hemoglobin, bilirubin, albumin, and ammonia significantly correlated with the changes of the bacterial concentration of the liver. The results of the study suggests that hepatic bacterial proliferation after BDR is significantly affected by microbial overgrowth in the bilioenteric anastomosis and is associated with deteriorated liver function and hemogram.

Anastomosis, Surgical↗
PubMed2026

Potential contribution of the microbiota-gut-brain axis to doxorubicin-associated cognitive impairment: Mechanisms, evidence, and therapeutic opportunities.

Chemotherapy-induced cognitive impairment (CICI), often termed chemobrain, is a clinically important complication of cancer treatment that can affect memory, attention, executive function, and processing speed during and after therapy. Doxorubicin is of particular mechanistic interest because brain parenchymal exposure is limited, yet preclinical studies consistently identify neuroinflammatory, oxidative, vascular, and synaptic abnormalities after treatment. This critical narrative review evaluates whether intestinal injury and disruption of the microbiota-gut-brain axis may contribute to these central effects. Preclinical evidence indicates that doxorubicin can alter microbial community structure, injure the intestinal barrier, modify SCFA-associated taxa or predicted functions, alter selected metabolite profiles, and promote systemic inflammatory and metabolic signaling. These peripheral changes could interact with brain endothelial cells, glia, mitochondria, hippocampal neurogenesis, and synaptic-plasticity pathways. However, the proposed doxorubicin-gut-brain pathway remains a predominantly preclinical and incompletely tested framework. No longitudinal human study has yet established, within the same patients, the temporal sequence linking doxorubicin exposure, microbiome or metabolome changes, systemic inflammation, and objective cognitive outcomes. Existing animal studies also vary in dose, regimen, tumor context, sampling time, microbiome methodology, and control of behavioral or microbiological confounders, while causal rescue experiments remain limited. Key priorities are therefore longitudinal human cohorts with pretreatment baselines and repeated multi-omics and cognitive assessments; animal studies that test temporal precedence and causal rescue or pathway blockade in the same model; mediation analyses that determine whether microbial or metabolic changes lie between treatment and cognitive dysfunction; and mechanism-informed clinical trials that demonstrate target engagement, cognitive benefit, oncology safety, and preservation of antitumor efficacy. Microbiome-directed interventions are promising but remain investigational for doxorubicin-associated CICI.

blood–brain barrier↗
PubMed1984

Functions of the large bowel: an overview.

The large intestine has been studied rather less than other portions of the alimentary canal for several reasons: a) considerable variations occur among species in the anatomy of the large bowel and in the absorptive contributions of the hindgut to homeostasis; b) in most species, the transit of colonic contents and the interactions between mucosa and contents are more complex than those occurring in the small bowel; and c) the existence of a rich microbial flora, which is of considerable importance ecologically, complicates the experimental approaches to colonic function and the interpretation of results. The colon possesses efficient mechanisms for sodium and chloride absorption, and an exchange of bicarbonate for luminal chloride is important. Absorptive function in the large bowel must also encompass the activities of faecal enzymes. By modifying faecal substrates, of both endogenous and exogenous origin, the flora facilitates and modifies absorption by the colon; in some species these events are important nutritionally. On the other hand, under pathophysiological conditions, the colon can secrete electrolytes and water. Storage and transit in the colon are also complex, relative to these phenomena in other areas of the gut. A major portion of the total mouth-to-anus transit time occurs in the colon, where to-and-fro movement of the contents is noticeable. Perhaps these complex movements facilitate absorption, by allowing optimum contact between contents and the mucosa. The colon also delivers material to the rectum in a manner whereby the distal bowel can prepare stools for convenient evacuation. Despite these difficulties, research is advancing our comprehension of the colon, its multiple and diverse functions and the possibilities for alterations of function leading to disease.

Animals↗
PubMed1996

Role of the glycocalyx in regulating access of microparticles to apical plasma membranes of intestinal epithelial cells: implications for microbial attachment and oral vaccine targeting.

Transepithelial transport of antigens and pathogens across the epithelial barrier by M cells may be a prerequisite for induction of mucosal immunity in the intestine. Efficient transport of antigens and pathogens requires adherence to M cell apical surfaces. Coupling of antigen-containing particles to the pentameric binding subunit of cholera toxin (CTB) has been proposed as a means for increasing antigen uptake because the CTB receptor, ganglioside GM1, is a glycolipid present in apical membranes of all intestinal epithelial cells. To test the accessibility of enterocyte and M cell membrane glycolipids to ligands in the size ranges of viruses, bacteria, and particulate mucosal vaccines, we analyzed binding of CTB probes of different sizes to rabbit Peyer's patch epithelium. Soluble CTB-fluorescein isothiocyanate (diameter 6.4 nm) bound to apical membranes of all epithelial cells. CTB coupled to 14 nm colloidal gold (final diameter, 28.8 nm) failed to adhere to enterocytes but did adhere to M cells. CTB-coated, fluorescent microparticles (final diameter, 1.13 microns) failed to adhere to enterocytes or M cells in vivo or to well-differentiated Caco-2 intestinal epithelial cells in vitro. However, these particles bound specifically to GM1 on BALB/c 3T3 fibroblasts in vitro and to undifferentiated Caco-2 cells that lacked brush borders and glycocalyx. Measurements of glycocalyx thickness by electron microscopy suggested that a relatively thin (20 nm) glycocalyx was sufficient to prevent access of 1-micron microparticles to glycolipid receptors. Thus, the barrier function of the intestinal epithelial cell glycocalyx may be important in limiting microbial adherence to membrane glycolipids, and in CTB-mediated targeting of vaccines to M cells and the mucosal immune system.

3T3 Cells↗
PubMed2006

Phylogenetic and functional biomakers as indicators of bacterial community responses to mixed-waste contamination.

Few studies have demonstrated changes in community structure along a contaminant plume in terms of phylogenetic, functional, and geochemical changes, and such studies are essential to understand how a microbial ecosystem responds to perturbations. Clonal libraries of multiple genes (SSU rDNA, nirK, nirS, amoA, pmoA, and dsrAB) were analyzed from groundwater samples (n = 6) that varied in contaminant levels, and 107 geochemical parameters were measured. Principal components analyses (PCA) were used to compare the relationships among the sites with respect to the biomarker (n = 785 for all sequences) distributions and the geochemical variables. A major portion of the geochemical variance measured among the samples could be accounted for by tetrachloroethene, 99Tc, No3, SO4, Al, and Th. The PCA based on the distribution of unique biomarkers resulted in different groupings compared to the geochemical analysis, but when the SSU rRNA gene libraries were directly compared (deltaC(xy) values) the sites were clustered in a similar fashion compared to geochemical measures. The PCA based upon functional gene distributions each predicted different relationships among the sites, and comparisons of Euclidean distances based upon diversity indices for all functional genes (n = 432) grouped the sites by extreme or intermediate contaminant levels. The data suggested that the sites with low and high perturbations were functionally more similar than sites with intermediate conditions, and perhaps captured the overall community structure better than a single phylogenetic biomarker. Moreover, even though the background site was phylogenetically and geochemically distinct from the acidic sites, the extreme conditions of the acidic samples might be more analogous to the limiting nutrient conditions of the background site. An understanding of microbial community-level responses within an ecological framework would provide better insight for restoration strategies at contaminated field sites.

Bacteria↗
PubMed2006

Development of the microbial communities in Lake Donghu in relation to water quality.

There is increasing recognition that protozoa is very useful in monitoring and evaluating water ecological healthy and quality. In order to study the relationship between structure and function of protozoan communities and water qualities, six sampling stations were set on Lake Donghu, a hypereutrophic subtropical Chinese lake. Microbial communities and protists sampling from the six stations was conducted by PFU (Polyurethane foam unit) method. Species number (S), diversity index (DI), percentage of phytomastigophra, community pollution value (CPV), community similarity and heterophy index (HI) were mensurated. The measured indicators of water quality included total phosphorus (TP), dissolved oxygen (DO), Chemical oxygen demand (COD), NH(4)(+), NO(2)(-) and NO(3)(-). Every month water samples from stations I, II, III, IV were chemically analyzed for a whole year, Among the chemically analyzed stations, station I was the most heavily polluted, station II was the next, stations III and IV had similar pollution degrees. The variable tendencies of COD, TP, NH(3), NO(2)(-), NO(3)(-), and DO during the year was approximately coincident among the six stations. Analysis from the community parameters showed that the pollution of station 0 was much more serious than others, and station V was the most slight. Of the community parameters, CPV and HI were sensitive in reflecting the variables of the water quality. Community similarity index was also sensitive in dividing water qualities and the water quality status of different stations could be correctly classified by the cluster analysis. DI could reflect the tendency of water quality gradient, species number and percentage of Phytomastigophora was not obvious in indicating the water quality gradient.

Animals↗
PubMed2003

Ecotoxicological risks associated with land treatment of petrochemical wastes. III. Immune function and hematology of cotton rats.

Landfarming is a widely used method of treating petrochemical waste through microbial bio-degradation. The effects of residual petrochemical contamination on wildlife, especially terrestrial mammals, are poorly understood. The effects of contaminants on the immune system and hematology of cotton rats (Sigmodon hispidus) living on five abandoned petrochemical landfarms (units 1-5) in Oklahoma were studied. Cotton rats were sampled seasonally (summer and winter) from each landfarm and from five ecologically matched reference sites for 2 yr (1998-2000) and returned to the laboratory for immunological and hematological assays. Overall analysis indicated that rats inhabiting landfarms exhibited decreased relative spleen size compared to rats collected from reference sites, with the landfarm at unit 1 showing the greatest reduction. Cotton rats collected from landfarms also had increased hemoglobin, hematocrit, and platelet levels and decreased blood leukocytes during summer. During winter, an increase in the number of popliteal node white blood cells was observed from rats collected on landfarms. No marked difference was detected for lymphocyte proliferation in response to concanavalin A, pokeweed, or interleukin-2. Lymphokine-activated killer cell lytic ability showed a seasonal pattern, but no treatment differences. No differences between landfarm and reference sites were detected in the hypersensitivity reaction of rats given an intradermal injection of phytohemagluttinin (PHA-P). Comparisons within individual sites indicated that two sites (units 1 and 3) had the greatest effects on immune function and hematology of cotton rats. The results of this study suggest that residual petrochemical waste affects the immune system and hematology of cotton rats living on abandoned landfarms during summer and is complicated by variation in the contaminants found on individual petroleum sites.

Agriculture↗
PubMed2006

Three-dimensional reconstruction of the nose epidermal cells in the microbial feeding nematode, Acrobeles complexus (Nematoda: Rhabditida).

The epidermis of the anterior end (nose) plays an important role in the evolution, development, and functional feeding morphology in nematodes, but information on this complex organ system is limited. Here, we produce a 3D model of 13 of the cells making up this organ system reconstructed from serial transmission electron micrographs of the microbial feeding nematode, Acrobeles complexus. Nose epidermal cells were found to be broadly similar to those of the distantly related model organism Caenorhabditis elegans in the number and arrangement of nuclei in these largely syncytial cells; this similarity demonstrates striking evolutionary conservation that allows for robust statements of homology between the taxa. Examining details of cell shape, however, revealed surprisingly complex subcellular specialization, which differed markedly from C. elegans in the number and arrangement of cell processes. Anterior toroid processes of the anterior arcade, posterior arcade, and HypB syncytia form a nested complex at the base of the labial probolae. Anterior toroid processes of HypC and the inner labial socket cells are associated with the base of the cephalic probolae and radial ridge processes. Extracellular filaments (tendon organs) and radiating cytoskeletal filaments of the posterior arcade syncytium form a connection between the body wall muscle cells and the pharynx. An epidermal cell with no known homolog in other nematodes is identified. Findings provide a basis to propose hypotheses related to the development and evolutionary origin of specialized feeding appendages (probolae) in the Cephalobinae (including Acrobeles), and hypotheses of homology are revised for epidermal cells in the nose of the closely related and primarily plant parasitic group, Tylenchida.

Anatomy, Comparative↗
PubMed2001

Fcgamma receptors in autoimmune diseases.

Fcgamma-receptors (Fcgamma-R) recognise the Fc portion of IgG and thus form a link between humoral and cellular immunity. These receptors are expressed by a variety of immune cells, and they function in the binding of immune complexes or IgG-opsonised particles, such as microbial pathogens. The are three major types of Fcgamma-R, namely Fcgamma-RI (CD64), Fcgamma-RII (CD32) and Fcgamma-RIII (CD16), and these differ in their ability to bind IgG and complexes. There are many isoforms of these receptors and a number of recently identified polymorphisms in their structure. This review describes the structure and function of these Fcgamma-Rs, and highlights how gene deficiencies and polymorphisms may contribute to the pathology of human diseases.

Autoimmune Diseases↗
PubMed2004

Impact of commensal microbiota on murine gastrointestinal tract gene ontologies.

The gastrointestinal tract (GIT) of eukaryotes is colonized by a vast number of bacteria, where the commensal microbiota play an important role in defining the healthy gut. To investigate the influence of commensal bacteria on multiple regions of the host GIT transcriptome, the gene expression profiles of the corpus, jejunum, descending colon, and rectum of conventional (n = 3) and germ-free mice (n = 3) were examined using the Affymetrix Mu74Av2 GeneChip. Differentially regulated genes were identified using the global error assessment model, and a novel method of Gene Ontology (GO) clustering was used to identify significantly modulated biological functions. The microbiota modify the greatest number of genes in the jejunum (267 genes with an alpha < 0.001) and the fewest in the rectum (137 genes with an alpha < 0.001). Clustering genes by GO biological process and molecular function annotations revealed that, despite the large number of differentially regulated genes, the residential microbiota most significantly modified genes involved in such biological processes as immune function and water transport all along the length of the mouse GIT. Additionally, region-specific communication between the host and microbiota were identified in the corpus and jejunum, where tissue kallikrein and apoptosis regulator activities were modulated, respectively. These findings identify important interactions between the microbiota and the mouse gut tissue transcriptome and, furthermore, suggest that interactions between the microbial population and host GIT are implicated in the coordination of region-specific functions.

Animals↗
PubMed2001

Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry?

Autoimmune diseases remain one of the mysteries that perplex immunologists. What makes the immune system, which has evolved to protect an organism from foreign invaders, turn on the organism itself? A popular answer to this question involves the lymphoid network's primordial function: autoimmunity is a by-product of the immune response to microbial infection. For decades there have been tantalizing associations between infectious agents and autoimmunity: beta-hemolytic streptococci and rheumatic fever; B3 Coxsackieviruses and myocarditis; Trypanosoma cruzi and Chagas' disease; diverse viruses and multiple sclerosis; Borrelia burgdorfii and Lyme arthritis; and B4 Coxsackievirus, cytomegalovirus or rubella and type 1 diabetes, to name the most frequently cited examples. In addition, animal models have provided direct evidence that infection with a particular microbe can incite a particular autoimmune disease. Nonetheless, many of the associations appear less than convincing and, even for those that seem to be on solid footing, there is no real understanding of the underlying mechanism(s).

Antigens, Surface↗
PubMed2025

A global survey of taxa-metabolic associations across mouse microbiome communities.

Host-microbiota mutualism is rooted in the exchange of dietary and metabolic molecules. Microbial diversity broadens the metabolite pool, with each taxon contributing distinct compounds in varying proportions. In the human microbiome, high variability in consortial composition is largely compensated by similar metabolic functions across different taxa. However, the extent of compensation in lower diversity mouse models, and whether vivaria are metabolically equivalent, is unknown. We provide a searchable resource of microbiome composition variability across 51 murine vivaria and 12 wild mouse colonies worldwide, with vivarium-specific variants mapped according to predicted 3D structures for each microbial species. Our matched metabolomics data show that realized metabolic potential has relatively low variability, providing functional evidence for metabolic compensation. Additionally, variability is related to taxonomic composition rather than vivarium, revealing taxa-metabolite associations that are potentially relevant to phenotypic differences between vivaria. Collectively, this resource offers tools to strengthen microbiome studies and collaborative science.

Animals↗
PubMed2006

NODs in defence: from vulnerable antimicrobial peptides to chronic inflammation.

Defensins and cathelicidins are prevalent and essential gastrointestinal cationic antimicrobial peptides (CAPs). However, these defensive peptides are not infallible because certain enteropathogens can overcome their protective function. Furthermore, impaired defensin synthesis has been linked to the occurrence of Crohn's disease (CD), a chronic inflammatory bowel disease. Recently, defective bacterial sensing through NOD1 and NOD2 has been related to reduced defensin production, CD predisposition and susceptibility to enteric infection. Hence, we propose that microbial sensors at the gut interface monitor the levels of these effector peptides, which might function as "danger" signals to confer tolerance and alert immunocytes. Further work is required to clarify how gastrointestinal CAPs are regulated and to assess their role in maintaining epithelial homeostasis and triggering adaptive immunity.

Amino Acid Sequence↗
PubMed2001

A strategy for the identification of proteins targeted by thioredoxin.

Thioredoxins are 12-kDa proteins functional in the regulation of cellular processes throughout the animal, plant, and microbial kingdoms. Growing evidence with seeds suggests that an h-type of thioredoxin, reduced by NADPH via NADP-thioredoxin reductase, reduces disulfide bonds of target proteins and thereby acts as a wakeup call in germination. A better understanding of the role of thioredoxin in seeds as well as other systems could be achieved if more were known about the target proteins. To this end, we have devised a strategy for the comprehensive identification of proteins targeted by thioredoxin. Tissue extracts incubated with reduced thioredoxin are treated with a fluorescent probe (monobromobimane) to label sulfhydryl groups. The newly labeled proteins are isolated by conventional two-dimensional electrophoresis: (i) nonreducing/reducing or (ii) isoelectric focusing/reducing SDS/PAGE. The isolated proteins are identified by amino acid sequencing. Each electrophoresis system offers an advantage: the first method reveals the specificity of thioredoxin in the reduction of intramolecular vs. intermolecular disulfide bonds, whereas the second method improves the separation of the labeled proteins. By application of both methods to peanut seed extracts, we isolated at least 20 thioredoxin targets and identified 5-three allergens (Ara h2, Ara h3, and Ara h6) and two proteins not known to occur in peanut (desiccation-related and seed maturation protein). These findings open the door to the identification of proteins targeted by thioredoxin in a wide range of systems, thereby enhancing our understanding of its function and extending its technological and medical applications.

Amino Acid Sequence↗
PubMed2002

Expression of functional Toll-like receptor 2 on human epidermal keratinocytes.

Epidermal keratinocytes secrete cytokines, chemokines, and anti-microbial peptides in response to various microbial pathogens and their components including lipopolysaccharide (LPS). To identify the receptor(s) involved in the anti-microbial responses of epidermal keratinocytes, we analyzed expression of CD14, Toll-like receptor 2 (TLR2), and TLR4 on cultured normal human epidermal keratinocytes (NHEK). Although CD14 and TLR2 mRNA were expressed in cultured NHEK, only TLR2 was detected on the cell surface. Cultured NHEK did not express TLR4 mRNA or protein. Commercial LPS preparations could stimulate epidermal keratinocytes to produce beta-defensin-2 and IL-8, and the LPS response was inhibited with mAb specific for TLR2, but not for CD14 or TLR4. Repurified LPS and lipid A did not stimulate epidermal keratinocytes, whereas peptidoglycan (PGN) from Gram-positive bacteria and yeast cell wall particle induced beta-defensin-2 and IL-8 production. Thus, cultured NHEK express functional TLR2, but not CD14 or TLR4, and the "LPS" response of epidermal keratinocytes shown in the previous studies might be mediated by TLR2-dependent recognition of non-LPS bacterial components contaminating in commercial LPS preparations. In the normal human skin, however, epidermal keratinocytes expressed both TLR2 and TLR4. Because TLR4 was induced in epidermal keratinocytes by in vitro stimulation with PGN from Gram-positive bacteria, constitutive expression of TLR4 on epidermal keratinocytes in vivo might also be induced by continuous recognition of the resident skin flora containing Gram-positive bacteria through TLR2.

Cells, Cultured↗