Immunotolerant p50/NFκB Signaling and Attenuated Hepatic IFNβ Expression Increases Neonatal Sensitivity to Endotoxemia

McKenna, Sarah; Burey, Taylor; Sandoval, Jeryl; Nguyen, Leanna; Castro, Odalis; Gudipati, Suma; Gonzalez, Jazmin; Kasmi, Karim C. El; Wright, Clyde J.

doi:10.3389/fimmu.2018.02210

Cited by 7 publications

(14 citation statements)

References 48 publications

(57 reference statements)

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“…Here, we present data demonstrating that exposure to IP LPS induced nuclear translocation of both p50 and p65 in the livers of juvenile and adult mice, but only p50 translocation was detected in the neonate. We have previously reported that the neonatal mice (p0) do not show hepatic p65-NF-κB signaling compared with the adult at 1 h post IP LPS exposure (26). The present work builds on our previous findings by demonstrating that LPS-induced NF-κB subunit p65 nuclear translocation, DNA binding and transcriptional activity does not occur at developmental ages p3 and p7 after LPS exposure.…”

Section: Discussionsupporting

confidence: 77%

“…Exposure to LPS induces a NF-κB-mediated pro-inflammatory signaling in the liver, and we have previously described that this response is attenuated in neonates compared with adults (26). However, how this response matures over time has never been described.…”

Section: Endotoxemia Induces Developmentally-regulated Hepatic Expresmentioning

confidence: 98%

“…Newborn (P0), neonatal (P3, P7), juvenile (P35), and adult (> 10 weeks) ICR male mice (Taconic Biosciences, Rensselaer, NY, USA) (n = 5-6/group) were exposed to a sublethal dose of intraperitoneal (IP) LPS (5 mg/kg; L2630, Sigma-Aldrich, St. Louis, MO, USA), as previously reported by our group (26,(40)(41)(42). Similar number of animals from each litter were included as a control (unexposed) group (P0, P3, P7, P35, and adult).…”

Section: Murine Model Of Endotoxemiamentioning

confidence: 99%

“…During fetal development and perinatal life, the liver plays a key role in regulating the innate immune response due to its essential role in clearing antigens from the systemic circulation (34)(35)(36)(37) via the portal vein, the biggest blood supply from the gut (38,39). It has been reported that the liver uniquely contributes to the NF-κB-mediated innate immune response to an inflammatory challenge through the activation of pro-inflammatory cytokines (26,40). Furthermore, we have observed that this response resembles a Th1type in adults when compared with neonates hours after intraperitoneally (IP) LPS exposure (26).…”

Section: Introductionmentioning

confidence: 99%

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Maturation of the Acute Hepatic TLR4/NF-κB Mediated Innate Immune Response Is p65 Dependent in Mice

et al. 2020

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Compared to adults, neonates are at increased risk of infection. There is a growing recognition that dynamic qualitative and quantitative differences in immunity over development contribute to these observations. The liver plays a key role as an immunologic organ, but whether its contribution to the acute innate immune response changes over lifetime is unknown. We hypothesized that the liver would activate a developmentally-regulated acute innate immune response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic expression and activity of the NF-κB, a key regulator of the innate immune response, at different developmental ages (p0, p3, p7, p35, and adult). Ontogeny of the NF-κB subunits (p65/p50) revealed a reduction in Rela (p65) and Nfkb1 (p105, precursor to p50) gene expression (p0) and p65 subunit protein levels (p0 and p3) vs. older ages. The acute hepatic innate immune response to LPS was associated by the degradation of the NF-κB inhibitory proteins (IκBα and IκBβ), and nuclear translocation of the NF-κB subunit p50 in all ages, whereas nuclear translocation of the NF-κB subunit p65 was only observed in the p35 and adult mouse. Consistent with these findings, we detected NF-κB subunit p65 nuclear staining exclusively in the LPS-exposed adult liver compared with p7 mouse. We next interrogated the LPS-induced hepatic expression of pro-inflammatory genes (Tnf, Icam1, Ccl3, and Traf1), and observed a gradually increase in gene expression starting from p0. Confirming our results, hepatic NF-κB subunit p65 nuclear translocation was associated with up-regulation of the Icam1 gene in the adult, and was not detected in the p7 mouse. Thus, an inflammatory challenge induces an NF-κB-mediated hepatic innate immune response activation across all developmental ages, but nuclear translocation of the NF-κB subunit p65 and associated induction of pro-inflammatory genes occurred only after the first month of life. Our results demonstrate that the LPS-induced hepatic innate immune response is developmentally regulated by the NF-κB subunit p65 in the mouse.

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Section: Discussionsupporting

confidence: 77%

Section: Endotoxemia Induces Developmentally-regulated Hepatic Expresmentioning

confidence: 98%

Section: Murine Model Of Endotoxemiamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Maturation of the Acute Hepatic TLR4/NF-κB Mediated Innate Immune Response Is p65 Dependent in Mice

et al. 2020

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“…The presence of active and robust NF-jB-mediated perinatal hepatic innate immune response responses to LPS is supported by our previous findings. We observed that, in neonatal (P0) mice, intraperitoneal (IP) LPS induced a robust hepatic innate immune response activation characterized by an early up-regulation of pro-inflammatory genes, 49,70 and degradation of cytosolic NF-jB inhibitory proteins IjBa and IjBb. 49 Furthermore, we found that the fetal lung and skin showed an early activation of the innate immune signaling after IA LPS exposure, although not as robust as the fetal liver when compared with their respective controls.…”

Section: Discussionmentioning

confidence: 99%

In uteroinflammatory challenge induces an early activation of the hepatic innate immune response in late gestation fetal sheep

et al. 2020

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Chorioamnionitis is associated with inflammatory end-organ damage in the fetus. Tissues in direct contact with amniotic fluid drive a pro-inflammatory response and contribute to this injury. However, due to a lack of direct contact with the amniotic fluid, the liver contribution to this response has not been fully characterized. Given its role as an immunologic organ, we hypothesized that the fetal liver would demonstrate an early innate immune response to an in utero inflammatory challenge. Fetal sheep (131 ± 1 d gestation) demonstrated metabolic acidosis and high cortisol and norepinephrine values within 5 h of exposure to intra-amniotic LPS. Likewise, expression of pro-inflammatory cytokines increased significantly at 1 and 5 h of exposure. This was associated with NF-κB activation, by inhibitory protein IκBα degradation, and nuclear translocation of NF-κB subunits (p65/p50). Corroborating these findings, LPS exposure significantly increased pro-inflammatory innate immune gene expression in fetal sheep hepatic macrophages in vitro. Thus, an in utero inflammatory challenge induces an early hepatic innate immune response with systemic metabolic and stress responses. Within the fetal liver, hepatic macrophages respond robustly to LPS exposure. Our results demonstrate that the fetal hepatic innate immune response must be considered when developing therapeutic approaches to attenuate end-organ injury associated with in utero inflammation.

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Increased penetration of diphenhydramine in brain via proton-coupled organic cation antiporter in rats with lipopolysaccharide-induced inflammation

Kawase

Chuma

Irie

et al. 2021

Brain, Behavior, & Immunity - Health

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Uptake transporters in brain microvascular endothelial cells (BMECs) are involved in the penetration of basic (cationic) drugs such as diphenhydramine (DPHM) into the brain. Lipopolysaccharide (LPS)-induced inflammation alters the expression levels and activities of uptake transporters, which change the penetration of DPHM into the brain. A brain microdialysis study showed that the unbound brain-to-plasma partition coefficient ( K p,uu,brain ) for DPHM in LPS rats was approximately two times higher than that in control rats. The transcellular transport of DPHM to BMECs was increased when BMECs were cultured with serum from LPS rats. Compared with control rats or BMECs, the brain uptake of DPHM in LPS rats was increased and the intracellular accumulation of DPHM was increased under a high intracellular pH in BMECs from LPS rats, respectively. Treatment of BMECs with transporter inhibitors or inflammatory cytokines had little impact on the intracellular accumulation of DPHM in BMECs. This study suggests that LPS-induced inflammation promotes unidentified proton-coupled organic cation (H + /OC) antiporters that improve the penetration of DPHM into rat brain via the blood-brain barrier.

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Immunotolerant p50/NFκB Signaling and Attenuated Hepatic IFNβ Expression Increases Neonatal Sensitivity to Endotoxemia

Cited by 7 publications

References 48 publications

Maturation of the Acute Hepatic TLR4/NF-κB Mediated Innate Immune Response Is p65 Dependent in Mice

Maturation of the Acute Hepatic TLR4/NF-κB Mediated Innate Immune Response Is p65 Dependent in Mice

In uteroinflammatory challenge induces an early activation of the hepatic innate immune response in late gestation fetal sheep

Increased penetration of diphenhydramine in brain via proton-coupled organic cation antiporter in rats with lipopolysaccharide-induced inflammation

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