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Biomedical subjects

B Henderson

Publications and source records attributed to B Henderson.

At least 91 records · Page 5Linked to original sources
PubMed1996

Microbial/host interactions in health and disease: who controls the cytokine network?

The interacting cellular and molecular systems which we classify as immunity and inflammation evolved to protect the organism from exogenous parasites including viruses and bacteria. Cytokines play a pivotal, but paradoxical, role both in immunity and inflammation. These local peptide hormone-like molecules form a major arm of the organisms, defenses against infectious microorganisms but they are also implicated as potent mediators of the pathology of infectious diseases. The apparently lethal effects of interleukin-1 and tumor necrosis factor in experimental septic shock testify to the latter. In the current paradigm, cytokine induction, as a protective or pathological mechanism, is a direct response to the presence of infectious microorganisms. Evidence is now accumulating that cytokines play a much more complex role in the interplay between exogenous microorganisms and the host. For example, it has been established that viruses have evolved pro-active methods of subverting the cytokine network by producing: (i) soluble cytokine receptors which bind and inactivate cytokines, (ii) immunomodulatory cytokine homologues, and (iii) ICE inhibitors. The possibility exists that the major role of these 'viral cytokines' is to neutralize certain host responses. Recent cytokine transgenic knockouts demonstrate that the normal benign response to commensal gut microflora becomes a lethal inflammatory state in the absence of the cytokines interleukin 2 or interleukin 10. The human body contains an enormous number of microorganisms which constitute the normal microflora. It is estimated that the average human contains 10(13) eukaryotic cells but 10(14) bacteria. We propose that the ability of the multicellular organism to live harmoniously with its commensal microflora must depend on mutual signalling involving eukaryotic cytokines and prokaryotic cytokine-like molecules. Such interactive signalling sets up non-inflammatory cytokine networks in tissues which form the background on which responses to infectious microorganisms must be built and related. The capacity of bacteria to induce cytokine synthesis was believed to be due to a small number of components, such as lipopolysaccharide (LPS), which is only active as a complex with host factors (lipopolysaccharide binding protein and CD14). However, it is now clear that bacteria contain and produce a large number of diverse molecules which can selectively induce the synthesis of both pro-inflammatory and immunomodulatory/anti-inflammatory cytokines. Many toxins are potent inducers of cytokine release or synthesis and some can inhibit LPS-induced cell activation. We have introduced the term bacteriokine to describe these bacterial cytokine inducers. The question that has to be addressed therefore is - who controls the cytokine network (eukaryotic or prokaryotic cells) and how is it controlled? It is proposed that an understanding of this question will bring with it an understanding of how to control the pathological inflammatory response and may allow the development of truly effective anti-inflammatory agents.

Animals↗
PubMed1996

Case report: acute cellulitis and lymphadenitis caused by mucoid Streptococcus pyogenes.

Most patients with acute cellulitis due to Streptococcus pyogenes have a striking onset of high fever and systemic toxicity. Even if hospitalization is deemed necessary for initial treatment, most patients respond promptly to appropriate antibiotic therapy and can be managed as outpatients for most of the treatment regimen. Described is a 48-year-old, previously healthy woman with acute cellulitis and lymphadenitis who did not initially respond to treatment despite proved in vitro activity against the patient's S. pyogenes isolate. The strain grew as a mucoid colony phenotype on blood agar plates. The mucoid characteristic of the strain may have accounted for the patient's lack of response to initial therapy, and previously published clinical and laboratory data support this impression.

Acute Disease↗
PubMed1996

Comparison of the pro-inflammatory cytokine-stimulating activity of the surface-associated proteins of periodontopathic bacteria.

Saline extraction of the periodontopathic bacterium, Actinobacillus actinomycetemcomitans, releases surface-associated material (SAM), a complex mixture of proteins and carbohydrates with potent biological actions on isolated bone and on various mammalian cell populations. In this study, the relative ability of the SAM from 5 organisms, implicated in the pathology of periodontal disease, to stimulate human mesenchymal and myelomonocytic cells to synthesize the proinflammatory cytokines - interleukin (IL)-1 beta, IL-6 and tumour necrosis factor (TNF)alpha has been investigated. The bacteria investigated were Actinobacillus actinomycetemcomitans, Eikenella corrodens, Porphyromonas gingivalis, Prevotella intermedia and Campylobacter rectus. Human cells were exposed to a four log order range of concentrations of the SAM, or of Escherichia coli lipopolysaccharide, to provide full agonist dose responses in order to allow comparison of the potency and efficacy of each SAM. All SAMs demonstrated the capacity to stimulate human gingival fibroblasts (HGFs), human peripheral blood mononuclear cells (PBMCs) or the myelomonocytic cell line - Mono-Mac-6 to release one or all of the cytokines assayed. Activity was heat- and trypsin-sensitive suggesting that the active components were proteinaceous. However, there were substantial differences in the potency and efficacy of each SAM when compared on a concentration basis (w/v). The most active SAM was from A. actinomycetemcomitans with those from E. corrodens and P. gingivalis being slightly less active. The least active cytokine-stimulating SAMs were from C. rectus and Pr. intermedia. One major difference between the SAMs and E. coli LPS was the inability of the former to stimulate HGFs to release IL-1 beta or TNF alpha although they could stimulate PBMCs to release these cytokines. This may have relevance to the pathology of the periodontal diseases.

Aggregatibacter actinomycetemcomitans↗
PubMed1996

Cytokine-inducing components of periodontopathogenic bacteria.

Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumour necrosis factor (TNF) are believed to be the major pathological mediators of inflammatory diseases ranging from arthritis to the periodontal diseases. The stimuli inducing proinflammatory cytokine induction in the former disease is unclear but in the periodontal diseases it is obvious that the stimulus is the accumulation of bacteria in the subgingival region. As these bacteria do not invade the lesional tissues in large numbers, it is believed that their soluble components or products interact with host tissues to induce cytokine gene transcription. The paradigm is that lipopolysaccharide is the key bacterial component inducing pro-inflammatory cytokine gene expression. However, over the past decade a growing number of reports on non-oral bacteria have established that many other bacterial components, as well as secretory products, have the capacity to induce cytokine synthesis. Some of these, such as the protein pneumolysin from Streptococcus pneumoniae, are incredibly potent (in this case inducing cytokine synthesis at femtomolar concentrations). This review surveys the range of bacterial components and products which have been shown to stimulate cytokine synthesis with particular emphasis on the hypothesis that these components play a role in the pathology of the periodontal diseases.

Animals↗
PubMed1996

Bacterially induced bone destruction: mechanisms and misconceptions.

Normal bone remodelling requires the coordinated regulation of the genesis and activity of osteoblast and osteoclast lineages. Any interference with these integrated cellular systems can result in dysregulation of remodelling with the consequent loss of bone matrix. Bacteria are important causes of bone pathology in common conditions such as periodontitis, dental cysts, bacterial arthritis, and osteomyelitis. It is now established that many of the bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. Some of these molecules, such as components of the gram-positive cell walls (lipoteichoic acids), are weak stimulators of bone resorption in vitro, while others (PMT, cpn60) are as active as the most active mammalian osteolytic factors such as cytokines like IL-1 and TNF. The complexity of the integration of bone cell lineage development means that there are still question marks over the mechanism of action of many well-known bone-modulatory molecules such as parathyroid hormone. The key questions which must be asked of the now-recognized bacterial bone-modulatory molecules are as follows: (i) what cell population do they bind to, (ii) what is the nature of the receptor and postreceptor events, and (iii) is their action direct or dependent on the induction of secondary extracellular bone-modulating factors such as cytokines, eicosanoids, etc. In the case of LPS, this ubiquitous gram-negative polymer probably binds to osteoblasts or other cells in bone through the CD14 receptor and stimulates them to release cytokines and eicosanoids which then induce the recruitment and activation of osteoclasts. This explains the inhibitor effects of nonsteroidal and anticytokine agents on LPS-induced bone resorption. However, other bacterial factors such as the potent toxin PMT may act by blocking the normal maturation pathway of the osteoblast lineage, thus inducing dysregulation in the tightly regulated process of resorption and replacement of bone matrix. At the present time, it is not possible to define a general mechanism by which bacteria promote loss of bone matrix. Many bacteria are capable of stimulating bone matrix loss, and the information available would suggest that each organism possesses different factors which interact with bone in different ways. With the rapid increase in antibiotic resistance, particularly with Staphylococcus aureus and M. tuberculosis, organisms responsible for much bone pathology in developed countries only two generations ago, we would urge that much greater attention should be focused on the problem of bacterially induced bone remodelling in order to define pathogenetic mechanisms which could be therapeutic targets for the development of new treatment modalities.

Alveolar Bone Loss↗
PubMed1996

Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis.

Cytokines are a diverse group of proteins and glycoproteins which have potent and wide-ranging effects on eukaryotic cell function and are now recognized as important mediators of tissue pathology in infectious diseases. It is increasingly recognized that for many bacterial species, cytokine induction is a major virulence mechanism. Until recent years, the only bacterial component known to stimulate cytokine synthesis was lipopolysaccharide (LPS). It is only within the past decade that it has been clearly shown that many components associated with the bacterial cell wall, including proteins, glycoproteins, lipoproteins, carbohydrates, and lipids, have the capacity to stimulate mammalian cells to produce a diverse array of cytokines. It has been established that many of these cytokine-inducing molecules act by mechanisms distinct from that of LPS, and thus their activities are not due to LPS contamination. Bacteria produce a wide range of virulence factors which cause host tissue pathology, and these diverse factors have been grouped into four families: adhesins, aggressins, impedins, and invasins. We suggest that the array of bacterial cytokine-inducing molecules represents a new class of bacterial virulence factor, and, by analogy with the known virulence families, we suggest the term "modulin" to describe these molecules, because the action of cytokines is to modulate eukaryotic cell behavior. This review summarizes our current understanding of cytokine biology in relation to tissue homeostasis and disease and concisely reviews the current literature on the cytokine-inducing molecules produced by gram-negative and gram-positive bacteria, with an emphasis on the cellular mechanisms responsible for cytokine induction. We propose that modulins, by controlling the host immune and inflammatory responses, maintain the large commensal flora that all multicellular organisms support.

Animals↗
PubMed1996

Cross-cultural investigations.

In Piaget's system, the development of children's cognitive structures is seen as progressing through a universal sequence from sensorimotor, to concrete, to formal logical thought. The data that have been obtained on his measures are problematic in their support for this view, however, because they indicate that adults in traditional societies often fail his formal tasks. Piaget's (1972) interpretation of such findings was that they indicated a problem with his measures, not his theory - if appropriate measures were available, he believed that formal logical operations would be found in all cultures and social groups. Our own interpretation differs. While we acknowledge that adults in all cultures are capable of thinking in a fashion that is more sophisticated, subtle, and complex than that of young children, we see the highest forms of thought as being dependent on the mastery of systems that are cultural creations and not universal human attainments - and we see Piaget's system of formal operations as being just one example of the sort of system that can be created by a culture and passed on from one generation to the next. In a previous investigation, Fiati (1992) studied children who were growing up in isolated, agricultural villages in the Volta region of West Africa. In these communities, life was still a traditional one, and children's experiences with time, money, and mathematical computation were considerably different from those of children who were attending schools in the nearby towns. Under these conditions, Fiati found that village children's skill in using numbers or in thinking about quantitative variables did not develop to a very high level as compared to that of their peers in the towns or as compared to their own thinking about social issues. In the terms used in the present Monograph, it appeared as though children's central conceptual structures for number - in contrast to their central conceptual structures for narrative - did not advance much past the unidimensional level. Are unidimensional structures, at least, universal? Very probably the answer to this question is yes. Although systems for counting, for example, vary widely, no culture has yet been found in which counting does not play some role or where young children fail to pass Piaget's conservation of number test (Saxe, 1988). It seems highly likely, therefore, that a mental counting line of some sort is a universal construction. The situation in the domain of narrative is quite similar. Although folktales vary widely from one culture to the next, no culture has been reported in which folktales play no role whatever or where the story line of existing folktales does not have some form of intentional component (Propp, 1922/1968). The mental story line may thus be a universal construction as well. Finally, no culture has been reported in which some form of decorative art is not present or in which no technology exists for launching a projectile along a desired trajectory. If these activities require a mental reference line of some sort, then this would be a candidate for universal conceptual attainment as well. In the present series of studies, our investigations were confined to societies that are modern, highly literate, and schooled. Thus, our interest was in demonstrating a universal progression well beyond the unidimensional level, in the sorts of structure that are crucial to life in a modern industrial culture. In fact, this was what we found in each of our studies. On our tests of central conceptual structures, children progressed through the same stages and at the same rate. By contrast, on our tests of more specific understanding, especially on those dealing with issues on which different cultures place different emphasis, we found large and significant cross-national differences. From this we conclude that, if a culture values a particular task or set of tasks and invests a great deal of effort in teaching them, it is likely that the

Adult↗
PubMed1995

Operational RNA code for amino acids: species-specific aminoacylation of minihelices switched by a single nucleotide.

The genetic code is based on aminoacylation reactions where specific amino acids are attached to tRNAs bearing anticodon trinucleotides. However, the anticodon-independent specific aminoacylation of RNA minihelix substrates by bacterial and yeast tRNA synthetases suggested an operational RNA code for amino acids whereby specific RNA sequences/structures in tRNA acceptor stems correspond to specific amino acids. Because of the possible significance of the operational RNA code for the development of the genetic code, we investigated aminoacylation of synthetic RNA minihelices with a human enzyme to understand the sequences needed for that aminoacylation compared with those needed for a microbial system. We show here that the species-specific aminoacylation of glycine tRNAs is recapitulated by a species-specific aminoacylation of minihelices. Although the mammalian and Escherichia coli minihelices differ at 6 of 12 base pairs, two of the three nucleotides essential for aminoacylation by the E. coli enzyme are conserved in the mammalian minihelix. The two conserved nucleotides were shown to be also important for aminoacylation of the mammalian minihelix by the human enzyme. A simple interchange of the differing nucleotide enabled the human enzyme to now charge the bacterial substrate and not the mammalian minihelix. Conversely, this interchange made the bacterial enzyme specific for the mammalian substrate. Thus, the positional locations (if not the actual nucleotides) for the operational RNA code for glycine appear conserved from bacteria to mammals.

Amino Acyl-tRNA Synthetases↗
PubMed1995

Surface-associated proteins from Staphylococcus aureus demonstrate potent bone resorbing activity.

Staphylococcus aureus infections are associated with rapid bone destruction in conditions such as osteomyelitis, bacterial arthritis, and infected orthopedic implant failure. How this bacterium induces bone destruction has not been defined. In studies of the role of oral Gram-negative bacteria in periodontal pathology, we have established that cell surface-associated proteins (SAPs) are potent stimulators of bone resorption. The surface-associated components from S. aureus have now been isolated and demonstrated to be extremely potent stimulators of bone resorption in the murine calvarial bone resorption assay. Bone resorption appears to be due to proteins, is not the result of contamination with lipoteichoic acid or muramyl dipeptide, and is potently inhibited by indomethacin and can be completely blocked by high concentrations of interleukin-1 receptor antagonist or TN3-19.12, a neutralizing monoclonal antibody to murine TNF. The SAP fraction can stimulate fibroblasts or monocytes to release osteolytic cytokines, but only at high concentrations. Fractionation of the SAPs by high performance liquid chromatography demonstrated that a number of fractions were osteolytically active. The most active contained a heterodimeric protein of molecular weight 32-36 kD. The presence of this osteolytically active surface-associated fraction may account for the bone resorption associated with local infection with S. aureus.

Animals↗
PubMed1995

Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.

Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones.

Cells, Cultured↗
PubMed1995

Relative cytokine-stimulating activities of surface components of the oral periodontopathogenic bacterium Actinobacillus actinomycetemcomitans.

The purpose of this study was to determine whether bacterial surface components other than lipopolysaccharide (LPS) could stimulate pro-inflammatory cytokine synthesis by mesenchymal and myelomonocytic cells in vitro. LPS, lipid A-associated proteins (LAP) and saline-extractable surface-associated material (SAM) were isolated from the periodontopathogenic bacterium Actinobacillus actinomycetemcomitans and added to cultures of human gingival fibroblasts (HGFs), human PBMCs and the human myelomonocytic MonoMac-6 cell line. Pro-inflammatory cytokine release into culture supernatants was determined by two-site ELISAs. Contrary to expectation, the highly purified LPS extracted from this bacterium was significantly less potent than the other surface extracts in stimulating release of IL-1 beta, IL-6 and TNF-alpha by all three cell types. The SAM was the most potent cytokine-stimulating agent showing equivalent activity to highly purified E. coli LPS in stimulating IL-6 release by PBMCs. LAP also had cytokine-stimulating activity although it was generally significantly less potent than the SAM. Thus in the case of this organism, which is involved in the pathology of chronic inflammatory diseases the LPS does not appear to be the major cytokine-stimulating component.

Aggregatibacter actinomycetemcomitans↗
PubMed1995

Modulins: a new class of cytokine-inducing, pro-inflammatory bacterial virulence factor.

Despite the fact that the inflammatory and immune responses have evolved to combat microorganisms, the present generation of inflammation researchers has evinced relatively little interest, with the exception of septic shock, in microbially-induced inflammation. This in spite of the fact that the Gram-negative cell wall constituent, lipopolysaccharide, has been widely used as a tool in inflammation research. The reason for such lack of interest has been due to the therapeutic efficacy of antibiotics which are the treatment of choice for infections and their inflammatory sequelae. However, this is likely to change within the next decade or so, with the relentless increase in the incidence of antibiotic-resistant strains of bacteria. This will return therapy to the stage where clinicians will have to treat the inflammatory symptoms of infection. Many of these symptoms are due to the stimulation of cytokine synthesis. The capacity of bacteria to induce cytokine synthesis has, until the past few years, centred exclusively on lipopolysaccharide. However, it has been established during the past 5-10 years that a range of other molecules, mainly associated with the surface of bacteria, have the capacity to induce cytokine production. Some of these are exquisitely potent stimulators of pro-inflammatory cytokine synthesis. The nature and mechanism of action of these various cytokine-inducing molecules, for which we have devised the name modulins, is the subject of this review. It is clear that bacteria still have many surprises for us, as exemplified by the recent discovery of the role played by Helicobacter pylori in gastritis, gastric ulceration and gastric cancer.

Animals↗
PubMed1995

Serum antibody response to surface-associated material from periodontopathogenic bacteria.

Saline extracts of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Eikenella corrodens contain surface-associated components of these bacteria. It has been shown that these extracts are potent stimulators of bone resorption in vitro. The possibility that the components of these surface-associated materials (SAM) could contribute to the serum immune response in patients with juvenile or adult onset forms of rapidly progressive periodontitis were investigated by direct binding ELISA. Very high titres of serum IgG antibodies to SAM from A. actinomycetemcomitans were detected in patients with localized juvenile periodontitis (LJP). Patients with adult onset rapidly progressive periodontitis (RPP) had significantly raised antibody levels to SAM from P. gingivalis. Both groups of patients had significantly raised levels of antibodies to SAM from E. corrodens compared with control sera. Thus, not only does solubilized SAM have the capacity to induce bone resorption, but it also contributes to the antigenic load on the immune system in LJP and RPP.

Adult↗
PubMed1995

Lipid A-associated proteins from periodontopathogenic bacteria induce interleukin-6 production by human gingival fibroblasts and monocytes.

The aim of this study was to determine whether lipid A-associated proteins (LAP) from two periodontopathogenic species of bacteria were able to stimulate interleukin-6 (IL-6) release from human gingival fibroblasts and myelomonocytic cells. LAP and lipopolysaccharide (LPS) were extracted from Porphyromonas gingivalis and Prevotella intermedia and added to cultures of human gingival fibroblasts and mono-mac-6 monocytic cells. Release of IL-6 into the culture supernatants was determined by ELISA. LAP and LPS from Por. gingivalis, but not from Prev. intermedia, stimulated IL-6 release from both cell types in a dose-dependent manner although LPS was less potent than LAP in inducing IL-6 release from the fibroblasts. IL-6 was detectable in cultures of both cell types following stimulation with LAP from Por. gingivalis at a concentration as low as 10 ng/ml. In response to LAP from Prev. intermedia, IL-6 was produced by mono-mac-6 cells but not by fibroblasts. Our results show that bacterial cell wall components other than LPS can induce IL-6 release from cells of the periodontium in vitro. The production of such potent immunomodulatory agents in vivo may contribute to the connective tissue breakdown characteristic of chronic periodontitis.

Bacterial Proteins↗