Bacterial Endotoxins and Host Immune Responses

Morrison, David C.; Ryan, John L.

doi:10.1016/s0065-2776(08)60802-0

Cited by 568 publications

(290 citation statements)

References 585 publications

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“…1 and 2). LPS is classically described as a heat-resistant molecule and boiling has been used in the literature to sort out the effects of contaminating LPS on cellular responsiveness (Morrison and Ryan, 1979;Rietschel et al, 1993). However, recent studies (Gao and Tsan, 2003a;Gao et al, 2006) have cast significant doubt on the validity of this method and we chose not to pursue this experimental route.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide is a frequent and significant contaminant in microglia‐activating factors

Weinstein

Swarts

Bishop

et al. 2007

Glia

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Lipopolysaccharide (LPS/endotoxin) is a potent immunologic stimulant. Many commercial-grade reagents used in research are not screened for LPS contamination. LPS induces a wide spectrum of proinflammatory responses in microglia, the immune cells of the brain. Recent studies have demonstrated that a broad range of endogenous factors including plasma-derived proteins and bioactive phospholipids can also activate microglia. However, few of these studies have reported either the LPS levels found in the preparations used or the effect of LPS inhibitors such as polymyxin B (PMX) on factor-induced responses. Here, we used the Limulus amoebocyte lysate assay to screen a broad range of commercial-and pharmaceutical-grade proteins, peptides, lipids, and inhibitors commonly used in microglia research for contamination with LPS. We then characterized the ability of PMX to alter a representative set of factor-induced microglial activation parameters including surface antigen expression, metabolic activity/proliferation, and NO/cytokine/chemokine release in both the N9 microglial cell line and primary microglia. Significant levels of LPS contamination were detected in a number of commercial-grade plasma/ serum-and nonplasma/serum-derived proteins, phospholipids, and synthetic peptide preparations, but not in pharmaceutical-grade recombinant proteins or pharmacological inhibitors. PMX had a significant inhibitory effect on the microglia-activating potential of a number of commercial-, but not pharmaceutical-grade, protein preparations. Novel PMX-resistant responses to α 2 -macroglobulin and albumin were incidentally observed. Our results indicate that LPS is a frequent and significant contaminant in commercial-grade preparations of previously reported microgliaactivating factors. Careful attention to LPS levels and appropriate controls are necessary for future studies in the neuroinflammation field.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide is a frequent and significant contaminant in microglia‐activating factors

Weinstein

Swarts

Bishop

et al. 2007

Glia

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“…Most other purified LPS chemotypes that stimulate polyclonal activation also stimulate strong primary IgM antibody responses (32); the lack of lipid A-related activity presumably explains why LVS LPS is such a weak immunogen. LVS LPS has more similarities to other nonmitogenic carbohydrate antigens such as capsular polysaccharides, which typically stimulate weak primary IgM and IgG3 responses as well.…”

Section: Discussionmentioning

confidence: 99%

“…During a bacterial infection, LPS may be recognized by host cells as a component of the bacterial surface, as well as following shedding of individual LPS molecules during bacterial growth or lysis. In mice, LPS purified from most pathogenic bacteria readily activates macrophages, B lymphocytes, neutrophils (32,36), and T cells indirectly (41) for proliferation and/or production of a variety of cytokines and chemokines. Strains of inbred mice that are genetically hyporesponsive to LPS, such as C3H/ HeJ, are paradoxically more susceptible to many gram-negative infections (38), indicating the importance of the molecule in influencing host-pathogen interactions.…”

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confidence: 99%

Purified Lipopolysaccharide fromFrancisella tularensisLive Vaccine Strain (LVS) Induces Protective Immunity against LVS Infection That Requires B Cells and Gamma Interferon

2000

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“…C3H/HeJ mice have a missense mutation in the third exon of TLR-4, yielding a nonfunctional TLR-4, and are hyporesponsive to the effects of LPS [24][25][26] and are resistant to lethal endotoxin-induced shock as compared with normal mice. 27 The simultaneous induction of the principal acute-phasecytokines suggests that a local paracrine mechanism may be responsible for these changes in the expression of genes involved in the regulation of hepatic iron metabolism.…”

mentioning

confidence: 99%

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Moriconi

Ahmad

Ramadori

et al. 2009

Laboratory Investigation

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The liver and the spleen are the organs in which cellular material and aged erythrocytes are eliminated from the blood. Within the liver, Kupffer cells (KCs) are mainly responsible for this task, as such KCs have a pivotal role in iron metabolism. The aim of this study is to investigate the changes of hepatic gene expression in two models of KC phagocytosis. Gadolinium chloride (GD) or zymosan was injected intraperitoneally into rats and to endotoxin-resistant mice (C3H/HeJ). The animals were killed at different time points and their livers were immediately frozen in liquid nitrogen for RNA isolation and immunohistological studies. RNA was analyzed by real-time PCR and northern blot. Sera were used to measure transaminases, hepcidin and iron levels. The expression of iron metabolism genes, hepcidin, hemojuvelin (Hjv), ferroportin-1 (Fpn-1) and of the inflammatory cytokines IL-6, IL-1b, TNF-a and IFN-g was determined. Although phagocytosed material was detected in ED-1-and C1q-positive cells, no inflammatory cells were identified within the liver parenchyma. Serum levels of hepcidin, iron and transaminases did not differ from those of control animals. Both GD and zymosan induced an upregulation of hepcidin-gene expression in rat liver as early as 3 h, reaching a maximum 6 h after treatment. Hjv-and Fpn-1-gene expression was downregulated at the same time. IL-6 was by far the most induced acute-phase-cytokine in GD-and zymosan-treated livers, although IL-1b and TNF-a were also strongly upregulated by zymosan and to a lesser extent by GD. Similar results were obtained in the C3H/HeJ mouse strain excluding the possible role of contaminating endotoxin. This study shows that phagocytosis upregulates hepcidin-gene expression and downregulates Hjv-and Fpn-1-gene expression within the liver. These changes in iron-regulating-gene expression may be mediated by the locally produced acute-phase-cytokines.

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Bacterial Endotoxins and Host Immune Responses

Cited by 568 publications

References 585 publications

Lipopolysaccharide is a frequent and significant contaminant in microglia‐activating factors

Lipopolysaccharide is a frequent and significant contaminant in microglia‐activating factors

Purified Lipopolysaccharide fromFrancisella tularensisLive Vaccine Strain (LVS) Induces Protective Immunity against LVS Infection That Requires B Cells and Gamma Interferon

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

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