CD14 transgenic mice expressing membrane and soluble forms: comparisons of levels of cytokines and lethalities in response to lipopolysaccharide between transgenic and non-transgenic mice

Tamura, Yuko; Higuchi, Yasunori; Kataoka, Masashi; Akizuki, Shin’ichiro; Matsuura, Keiko; Yamamoto, Shunsuke

doi:10.1093/intimm/11.3.333

Cited by 23 publications

(33 citation statements)

References 24 publications

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“…sCD14 can also transfer cell-bound LPS to plasma lipoproteins (78). The fact that survival rates in the lethal Shwartzman reaction induced by LPS were significantly higher in CD14 transgenic than in nontransgenic mice is compatible with this hypothesis (79).…”

Section: Discussionmentioning

confidence: 78%

CD14 Is an Acute-Phase Protein

Bas

Gauthier²,

Spenato

et al. 2004

The Journal of Immunology

229

209

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The origin of soluble CD14 (sCD14) in the circulation is uncertain. To examine whether CD14 could be an acute-phase protein (APP), the levels of sCD14, IL-6, and C-reactive protein were determined by ELISA in serum and synovial fluid (SF) of patients with various arthropathies, and the regulation of CD14 synthesis was examined in liver cells. In patients with crystal-mediated or immunologically mediated arthritis (rheumatoid arthritis), serum levels of sCD14 were higher than or similar to those found in infection-mediated arthritis (reactive arthritis), precluding a relation with bacteria exposure. Levels of sCD14 were similar in SF and serum, and did not correlate with the number of SF leukocytes, excluding an important source from leukocyte membrane-bound CD14, by protease-mediated shedding. In contrast, serum levels of sCD14 in patients correlated with those of C-reactive protein, a classical APP, and IL-6, a cytokine known to regulate the synthesis of APP in the liver. Serum levels of sCD14 also correlated with disease activity in rheumatoid arthritis and reactive arthritis patients. IL-6 stimulated the production of CD14 by HepG2 hepatoma cells. By real-time PCR, the inducibility of CD14 by IL-6 was also observed at the mRNA level both in HepG2 cells and human primary hepatocytes. These in vitro results were confirmed by in vivo studies in IL-6−/− mice injected with turpentine, an experimental model of acute-phase response. Liver levels of CD14 mRNA increased in IL-6+/+, but not in IL-6−/− mice. These results indicate that sCD14 can be considered as a type 2 APP.

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Section: Discussionmentioning

confidence: 78%

CD14 Is an Acute-Phase Protein

Bas

Gauthier²,

Spenato

et al. 2004

The Journal of Immunology

229

209

View full text Add to dashboard Cite

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“…With respect to protection against LPS, the role of sCD14 is less established and has been addressed in several publications. Two independent groups generated transgenic mice expressing CD14 under control of either the Moloney murine leukemia virus long terminal repeat [10] or the metallothionein promoter [11] and reported an increase and decrease in sensitivity to LPS in vivo, respectively. To clarify this contradiction and to see if hCD14 is capable of complementing LPS signaling in mice in the absence of endogenous CD14, we generated transgenic mice using BAC DNA covering the CD14 locus and containing the genomic areas 40 kb upstream and downstream of the CD14 initiation transcription site.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that a hCD14 transgene driven by a heterologous promoter is capable of protecting animals from the lethal effects of LPS [11]. Prior to that, a second group using a similar system found that transgenic mice are hypersensitive to LPS, thus providing an opposite effect and conflicting data [10].…”

Section: Cellular Responses To Lps In Hcd14-transgenic Micementioning

confidence: 99%

“…Such high levels of sCD14 suggest that in addition to mediating signaling from LPS, sCD14 may function as an acutephase protein or have other functions [9]. Several attempts have been made to over-express sCD14 in vivo under control of a heterologous promoter in order to examine its possible protective role in LPS-initiated endotoxin shock [10,11]. These studies yielded conflicting results, since both protection against endotoxin shock and hypersensitivity to LPS have been reported.…”

Section: Introductionmentioning

confidence: 99%

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Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS‐induced lethality

et al. 2006

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Despite significant progress in understanding the origin of soluble CD14 (sCD14), its physiological function remains largely unknown. Recent research has produced contradictory observations suggesting that sCD14 may have either beneficial or detrimental properties in protection against LPS-induced endotoxin shock. To resolve this controversy and to establish a mouse model suitable for elucidation of the functions of human CD14 (hCD14) in vivo, we generated several lines of transgenic mice bearing different copy numbers of the hCd14 transgene on a murine Cd14 -/-background. The hCD14 was entirely capable of complementing loss of mouse CD14 to mediate cellular responses to LPS. Serum levels of sCD14 in a founder with multiple copies of the transgene were several times higher than in transgenic animals with a single copy of Cd14. Furthermore, mice with high levels of hCD14 were hypo-responsive to LPS and survived a lethal dose of LPS. Further inquiry into the mechanism of the hypo-response to LPS revealed that protection is associated with the higher amounts of circulating LPS. Most of this circulating LPS can be immunoprecipitated with anti-CD14 antibodies. These results suggest that sCD14 blocks circulating LPS by limiting the amount of monocyte-bound LPS and thus reduces inflammatory responses.

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“…Transgenic mice overexpressing CD14 are more sensitive to LPS-induced shock than CD14-expressing controls (15,48), while mice deficient in CD14 (CD14 knockout [CD14KO] mice) show little or no response to a dose of LPS that is 10-fold higher than a 100% lethal dose for CD14-expressing mice (21). Furthermore, intraperitoneal or intravenous administration of a dose of Escherichia coli O111 that is lethal for control mice produces little or no response in CD14KO mice, indicating that CD14 mediates the LPS-induced state (21).…”

mentioning

confidence: 99%

Critical Role of CD14 for Production of Proinflammatory Cytokines and Cytokine Inhibitors during Sepsis with Failure To Alter Morbidity or Mortality

et al. 2001

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We investigated the immunopathophysiologic responses during sepsis induced by cecal ligation and puncture (CLP) in CD4-deficient (CD14 knockout [CD14KO]) mice. Our studies were designed to specifically test the role of CD14 in the inflammatory response to sepsis and to ascertain if alterations would improve morbidity or mortality. Sepsis was induced using the CLP model with appropriate antibiotic treatment. The severity of sepsis increased in the CD14KO mice with increasing puncture size (18 gauge [18G], 21G, and 25G). Following CLP, body temperature (at 12 h) and gross motor activity levels of the sham and 25G CLP groups recovered to normal, while the 21G and 18G CLP groups exhibited severe hypothermia coupled with decreased gross motor activity and body weight. There were no significant differences in survival, temperature, body weight, or activity levels between CD14KO and control mice after 21G CLP. However, CD14KO mice expressed two-to fourfold less pro-inflammatory (interleukin-1␤ [IL-1␤], tumor necrosis factor [TNF], and IL-6) and antiinflammatory (IL-10, IL-1 receptor antagonist, and TNF receptors I and II) cytokines in the blood after 21G CLP. Plasma levels of the chemokines macrophage inflammatory protein 2␣ and KC were similarly reduced in CD14KO mice. A similar trend of decreased cytokine and cytokine inhibitor levels was observed in the peritoneal cavity of CD14KO mice. Our results indicate that the CD14 pathway of activation plays a critical role in the production of both pro-inflammatory cytokines and cytokine inhibitors but has minimal impact on the morbidity or mortality induced by the CLP model of sepsis.Surgery, trauma, or other sources of inflammation can ultimately lead to sepsis, a common cause of morbidity and mortality. Temperature alterations, inflammation, and elevated cytokine levels are some characteristics of sepsis (6). While the etiology of sepsis is multifactorial, endotoxin (lipopolysaccharide [LPS]), a major component of the outer membrane of gram-negative bacteria (39, 43), is capable of inducing a sepsislike picture. Although endotoxin in appropriate amounts can activate favorable responses by increasing the ability of macrophages to mount antimicrobial activities (35, 43), large amounts of LPS can be toxic, ultimately leading to endotoxic shock (6, 39). Appropriate host recognition and responses to LPS therefore represent a key event in determining the level and type of available protection (43).CD14 is an LPS receptor (54) and is anchored to the monocyte/macrophage cell membrane via glycosylphosphatidyl inositol (18,20). In vitro studies have shown that cells bearing the CD14 receptor bind LPS in the presence of LPS-binding protein (44) and are activated to produce pro-and anti-inflammatory cytokines and chemokines and a variety of other molecules active in the innate immune response. Recently, it has been shown that signal transduction via membrane CD14 requires a signaling complex which appears to include, at a minimum, the expression of Toll 4 (9, 24, 32, 36), MD2 (47), a...

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CD14 transgenic mice expressing membrane and soluble forms: comparisons of levels of cytokines and lethalities in response to lipopolysaccharide between transgenic and non-transgenic mice

Cited by 23 publications

References 24 publications

CD14 Is an Acute-Phase Protein

CD14 Is an Acute-Phase Protein

Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS‐induced lethality

Critical Role of CD14 for Production of Proinflammatory Cytokines and Cytokine Inhibitors during Sepsis with Failure To Alter Morbidity or Mortality

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