In-vivo induction of apoptosis in murine lymphocytes by bacterial lipopolysaccharides

Norimatsu, Mari; Ono, Tomoko; Aoki, Akemi; Ohishi, Kazuhito; Tsutsumi, Yutaka

doi:10.1099/00222615-43-4-251

Cited by 49 publications

(41 citation statements)

References 21 publications

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“…This reduction in CD4 ϩ CD8 ϩ thymocytes was likely a result of apoptotic cell death, as previously demonstrated by others (25,42,43) and as suggested by our findings of up-regulation of proapoptotic genes of the Fas and mitochondrial pathways in thymocytes from mice exposed to LPS. The main findings of this study are that LPS exposure results in a significant increase in intrathymic levels of TXB 2 and that, when thromboxane signaling is absent (as in TP Ϫ/Ϫ mice), the apoptotic response to LPS is significantly attenuated.…”

Section: Discussionsupporting

confidence: 72%

“…However, experimental data by Hotchkiss et al indicate that lymphocyte apoptosis impairs host responses during sepsis and contributes to mortality (17,20). Several mediators, such as TNF (42), adrenal steroids (22,25), the complement split product C5a (15,31), and nitric oxide (44), have been implicated in sepsis-or LPSinduced thymocyte apoptosis. However, the role of prostanoid inflammatory mediators in this process had not been previously investigated.…”

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confidence: 99%

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Role of Thromboxane A₂in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Rocha

Plumb

Robinson

et al. 2005

Clin Vaccine Immunol

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Lipopolysaccharide (LPS) causes apoptotic deletion of CD4؉ CD8 ؉ thymocytes, a phenomenon that has been linked to immune dysfunction and poor survival during sepsis. Given the abundance of thromboxaneprostanoid (TP) receptors in CD4 ؉ CD8 ؉ thymocytes and in vitro evidence that thromboxane A 2 (TXA 2 ) causes apoptosis of these cells, we tested whether enhanced generation of TXA 2 plays a role in LPS-induced thymocyte apoptosis. Mice injected with 50 g of LPS intraperitoneally displayed a marked increase in generation of TXA 2 and prostaglandin E 2 in the thymus as well as apoptotic deletion of CD4 ؉ CD8 ؉ thymocytes. Administration of indomethacin or rofecoxib inhibited prostanoid synthesis but did not affect thymocyte death. In contrast, thymocyte apoptosis in response to LPS was significantly attenuated in TPdeficient mice. These studies indicate that TXA 2 mediates a portion of apoptotic thymocyte death caused by LPS. The absence of an effect of global inhibition of prostanoid synthesis suggests a complex role for prostanoids in this model.Bacterial sepsis is associated with apoptotic cell death in a variety of organs and tissues, including the thymus (16,19,42). The LPS component of gram-negative bacteria appears to mediate most of these effects, since injection of LPS into mice is followed by a dramatic reduction in thymocyte numbers, simulating the situation during sepsis. LPS does not cause thymocyte apoptosis directly, as addition of LPS to in vitro cultures of thymocytes does not result in apoptosis of these cells (43). This result is not surprising, as thymocytes are not known to express the main LPS receptor, TLR4. Therefore, thymocyte apoptosis following LPS injection in vivo is likely mediated by soluble factors produced by TLR4-expressing cells of the innate immune system. The identification of such mediators could have implications for therapy, since recent evidence suggests that lymphocyte apoptosis during sepsis is deleterious because it might impair immune responses and contribute to mortality (20).Prostanoids are produced by cells of the innate immune system exposed to LPS (27). TXA 2 is a prostanoid mediator derived by the sequential metabolism of cell membrane phospholipids by phospholipases, COX, and thromboxane synthase. During inflammatory states, this metabolic pathway is induced, resulting in enhanced TXA 2 production (39). TXA 2 has long been known for its vasoconstrictive and procoagulant properties, but a recent study revealed a novel and important role for this molecule in cell-mediated immunity (38). In addition, several lines of investigation point toward TXA 2 as a potential mediator of thymocyte apoptosis. First, Nusing et al. showed that the activity of TXA 2 synthase in dendritic cells of the thymic stroma is as high as it is in platelets (26). Second, Namba and coworkers demonstrated that the thymus is the organ with the highest concentration of TP receptors (24). In the thymus, immature CD4 ϩ CD8 ϩ thymocytes have the highest concentrations of TP receptors among cells; when...

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Section: Discussionsupporting

confidence: 72%

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confidence: 99%

Role of Thromboxane A₂in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Rocha

Plumb

Robinson

et al. 2005

Clin Vaccine Immunol

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“…Leukopenia and fever are usually attributed to the E. coli endotoxin LPS [18] which induces high levels of TNF-α within 8-16 h after infection [3,17]. The pro-apoptotic effect of TNF-α for lymphocytes and neutrophils [29,36,51] may explain the leukopenia in our model. In contrast, the upregulation of TLR2, TLR4, and β-defensins occurs spatially restricted, in specific udder quarters, and hence are independent from systemic, circulating TNF-α and other inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 67%

Escherichia coli, but notStaphylococcus aureustriggers an early increased expression of factors contributing to the innate immune defense in the udder of the cow

et al. 2008

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-The outcome of an udder infection is influenced by the pathogen species. We established a strictly defined infection model to better analyze the unknown molecular causes for these pathogen-specific effects, using Escherichia coli and Staphylococcus aureus strains previously asseverated from field cases of mastitis. Inoculation of quarters with 500 CFU of E. coli (n = 4) was performed 6 h, 12 h, and 24 h before culling. All animals showed signs of acute clinical mastitis 12 h after challenge: increased somatic cell count (SCC), decreased milk yield, leukopenia, fever, and udder swelling. Animals inoculated with 10 000 CFU of S. aureus for 24 h (n = 4) showed no or only modest clinical signs of mastitis. However, S. aureus caused clinical signs in animals, inoculated for 72 h-84 h. Real-time PCR proved that E. coli inoculation strongly and significantly upregulated the expression of β-defensins, TLR2 and TLR4 in the pathogen inoculated udder quarters as well as in mammary lymph nodes. TLR3 and TLR6 were not significantly regulated by the infections. Immuno-histochemistry identified mammary epithelial cells as sites for the upregulated TLR2 and β-defensin expression. S. aureus, in contrast, did not significantly regulate the expression of any of these genes during the first 24 h after pathogen inoculation. Only 84 h after inoculation, the expression of β-defensins, but not of TLRs was significantly (> 20 fold) upregulated in five out of six pathogen inoculated quarters. Using the established mastitis model, the data clearly demonstrate a pathogen-dependent difference in the time kinetics of induced pathogen receptors and defense molecules.toll-like receptor / mastitis / beta-defensin / mammary epithelial cell

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“…In mice exposed to LPS, the TNFa levels have been demonstrated to be elevated significantly 1 hour postinjection, and the time course of plasma corticosterone concentration correlates well with the development of apoptosis noted in the thymus (37).…”

Section: Apocynin Treatmentmentioning

confidence: 99%

The Prophylactic Effects of Natural Water-Soluble Antioxidant from Spinach and Apocynin in a Rabbit Model of Lipopolysaccharide-Induced Endotoxemia

Lomnitski

Carbonatto²,

Ben-Shaul

et al. 2000

Toxicol Pathol

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In-vivo induction of apoptosis in murine lymphocytes by bacterial lipopolysaccharides

Cited by 49 publications

References 21 publications

Role of Thromboxane A₂in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Role of Thromboxane A₂in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Escherichia coli, but notStaphylococcus aureustriggers an early increased expression of factors contributing to the innate immune defense in the udder of the cow

The Prophylactic Effects of Natural Water-Soluble Antioxidant from Spinach and Apocynin in a Rabbit Model of Lipopolysaccharide-Induced Endotoxemia

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In-vivo induction of apoptosis in murine lymphocytes by bacterial lipopolysaccharides

Cited by 49 publications

References 21 publications

Role of Thromboxane A2in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Role of Thromboxane A2in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Escherichia coli, but notStaphylococcus aureustriggers an early increased expression of factors contributing to the innate immune defense in the udder of the cow

The Prophylactic Effects of Natural Water-Soluble Antioxidant from Spinach and Apocynin in a Rabbit Model of Lipopolysaccharide-Induced Endotoxemia

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Role of Thromboxane A₂in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide

Role of Thromboxane A₂in the Induction of Apoptosis of Immature Thymocytes by Lipopolysaccharide