Bacterial Induction of Beta Interferon in Mice Is a Function of the Lipopolysaccharide Component

Sing, Andreas; Merlin, Thomas; Knopf, Hans-Peter; Nielsen, Peter; Loppnow, Harald; Galanos, Chris; Freudenberg, Marina A.

doi:10.1128/iai.68.3.1600-1607.2000

Cited by 78 publications

(72 citation statements)

References 41 publications

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“…Moreover, although L. monocytogenes-induced IFN-␤ responses are listeriolysin dependent, a GBS mutant defective in hemolysin, a listeriolysin homologue, was fully capable in this study of inducing IFN-␤. Traditionally, bacterial induction of IFN-␤ has been considered solely a function of the LPS component of Gram-negative bacteria, based on observations that high doses (100 g/ml) of heatkilled Gram-positive bacteria were unable to induce IFN-␣␤ expression in macrophages (53). We found, however, that, in addition to live bacteria, low (0.1 g/ml), but not high (Ն10 g/ml), doses of heatkilled bacteria can also induce IFN-␣␤ expression in macrophages (our unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Mancuso

Midiri

Biondo

et al. 2007

The Journal of Immunology

223

214

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It is known that host cells can produce type I IFNs (IFN-αβ) after exposure to conserved bacterial products, but the functional consequences of such responses on the outcome of bacterial infections are incompletely understood. We show in this study that IFN-αβ signaling is crucial for host defenses against different bacteria, including group B streptococci (GBS), pneumococci, and Escherichia coli. In response to GBS challenge, most mice lacking either the IFN-αβR or IFN-β died from unrestrained bacteremia, whereas all wild-type controls survived. The effect of IFN-αβR deficiency was marked, with mortality surpassing that seen in IFN-γR-deficient mice. Animals lacking both IFN-αβR and IFN-γR displayed additive lethality, suggesting that the two IFN types have complementary and nonredundant roles in host defenses. Increased production of IFN-αβ was detected in macrophages after exposure to GBS. Moreover, in the absence of IFN-αβ signaling, a marked reduction in macrophage production of IFN-γ, NO, and TNF-α was observed after stimulation with live bacteria or with purified LPS. Collectively, our data document a novel, fundamental function of IFN-αβ in boosting macrophage responses and host resistance against bacterial pathogens. These data may be useful to devise alternative strategies to treat bacterial infections.

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Section: Discussionmentioning

confidence: 99%

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Mancuso

Midiri

Biondo

et al. 2007

The Journal of Immunology

223

214

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“…Re-form LPS of E. coli, serotype 515 (liquid) and lipid A from E. coli, serotype 515 (liquid) were from Alexis Deutschland GmbH (Grünberg, Germany). S. minnesota (S-form) and S. minnesota mutant R 595 (Re-form) bacteria for stimulation of MC were prepared as described [66]. The following mAb were used: commercial IgE with specificity for DNP (SPE-7; Sigma, Deisenhofen, Germany), anti-TLR4/MD-2 (clone MTS510; Alexis Deutschland GmbH), anti-RP105 (clone RP/14; eBioscience, San Diego, CA) and PE-conjugated anti-CD14 antibody (clone rmC5-3; Pharmingen, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

R‐form LPS, the master key to the activation ofTLR4/MD‐2‐positive cells

et al. 2006

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Lipopolysaccharide (endotoxin, LPS) is a major recognition marker for the detection of gram-negative bacteria by the host and a powerful initiator of the inflammatory response to infection. Using S-and R-form LPS from wild-type and R-mutants of Salmonella and E. coli, we show that R-form LPS readily activates mouse cells expressing the signaling receptor Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), while the S-form requires further the help of the LPS-binding proteins CD14 and LBP, which limits its activating capacity. Therefore, the R-form LPS under physiological conditions recruits a larger spectrum of cells in endotoxic reactions than S-form LPS. We also show that soluble CD14 at high concentrations enables CD14-negative cells to respond to S-form LPS. The presented in vitro data are corroborated by an in vivo study measuring TNF-a levels in response to injection of R-and S-form LPS in mice. Since the R-form LPS constitutes ubiquitously part of the total LPS present in all wild-type bacteria its contribution to the innate immune response and pathophysiology of infection is much higher than anticipated during the last half century.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35593_pdf IntroductionThe interaction of highly conserved microbial constituents with the innate immune system forms the basis of recognition of and reaction against intruding pathogens in mammals. One such constituent is lipopolysaccharide (endotoxin, LPS), a major recognition marker common to gram-negative bacteria [1][2][3], a large group comprising important human pathogens as well as commensals. Thus, the interaction of LPS with cells of the innate immune system leads to the formation and release of endogenous mediators initiating inflammatory and immune responses essential for an antibacterial defense [3,4]. This primarily protective mechanism may become overshadowed by an acute pathophysiological response with the typical clinical symptoms of septic shock that frequently follows the release of inflammatory mediators, such as tumor necrosis factor (TNF)-a during infection [5][6][7].Innate immunity * Both authors contributed equally to this work. [10]. Binding of allergen to its specific IgE on the surface of MC results in an immediate release of preformed pro-inflammatory mediators (e.g., histamine, TNF-a and proteases) from cytoplasmic granules (degranulation) [11] and a later release of de novo synthesized arachidonic acid metabolites and various cytokines like interleukin 6 (IL-6), TNF-a, and chemokines [10,11]. Unlike allergens, LPS induces no degranulation of MC, but like allergens, it stimulates the de novo synthesis and release of cytokines in these cells [9].Activation of cells by LPS is mediated by the Toll-like receptor 4 (TLR4), a member of the highly conserved protein family of TLR, which are specialized in the recognition of microbial components. In mice, defects in TLR4 result in LPS unresponsiveness [12]. For functional interaction with LP...

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“…Total RNA was isolated from freshly removed organs or cultured macrophages by a guanidinium isothiocyanatephenol-choloroform-isoamyl alcohol procedure [37] as described in detail in [38]. The RNA concentration was determined by absorbance at 260 nm.…”

Section: Rna Extractionmentioning

confidence: 99%

Toll‐like receptor 4 expression levels determine the degree of LPS‐susceptibility in mice

et al. 2003

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C57BL/10ScCr (Cr) mice carry a deletion of the Toll-like receptor 4 (tlr4) gene (i.e. they are tlr4 0/0 ) and are thus refractory to LPS effects. Insertion of wild-type tlr4 transgene into the tlr4 0/0 Cr germ line endowed LPS susceptibility in the two transgenic lines created, indicating that TLR4 is the only limiting factor for LPS responsiveness in Cr mice. The absolute levels of tlr4 mRNA expressed by the heterozygous transgenic (tlr4 Tr/0 ), wild-type C57BL/10ScSn (Sn) (tlr4 +/+ ) and heterozygous F1 (Sn × Cr) (tlr4 +/0 ) mice varied markedly. However, the pattern of distribution of expression in the different organs was the same in all strains. In different biological assays (B cell mitogenicity, cytokine induction and lethal toxicity) the degree of LPS response obtained in the different strains of mice correlated with the levels of tlr4 mRNA expression. In macrophages, investigation of the LPS-induced cytokine (IL-6) response revealed a linear relationship between the response and the logarithm of TLR4-MD-2 levels.

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Bacterial Induction of Beta Interferon in Mice Is a Function of the Lipopolysaccharide Component

Abstract: We investigated the reason for the inability of lipopolysaccharide (LPS)-resistant (Lps-defective [Lps

Cited by 78 publications

References 41 publications

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

R‐form LPS, the master key to the activation ofTLR4/MD‐2‐positive cells

Toll‐like receptor 4 expression levels determine the degree of LPS‐susceptibility in mice

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