Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NFκB-Dependent Mechanism

McKenna, Sarah; Eckman, Mark H.; Parker, Aimée; Bok, Rachael; Hurt, K. Joseph; Wright, Clyde J.

doi:10.1159/000445541

Cited by 11 publications

(16 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously demonstrated that low doses of the IKK inhibitor BAY 11-7085 (1 micromolar) selectively targets IκBβ/NFκB signaling and attenuates the expression of select proinflammatory target genes ( 27 – 30 ). Extending that dose-response experiment, we determined that a minimum of BAY 11-7085 0.5 micromolar is necessary to significantly attenuate LPS-induced IL1β mRNA expression in RAW 264.7 cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It has recently been recognized that the nuclear activity of IκBβ contributes to sustained NFκB activity and pro-inflammatory target gene expression ( 25 , 26 ). Furthermore, we have published that IκBβ/NFκB signaling can be pharmacologically targeted to attenuate the sustained expression of pro-inflammatory genes ( 27 – 30 ). Here, we report that pulmonary expression of IL1β is reduced in endotoxemic neonatal mice with attenuated/absent IκBβ/NFκB signaling in IκBβ overexpressing (AKBI) and IκBβ −/− mice, while NFκB regulated expression of key antiapoptotic proteins remained intact.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Recently, we have demonstrated that IκBβ/NFκB signaling can be pharmacologically targeted in vitro , while leaving IκBα/NFκB signaling intact ( 27 – 30 ). By preventing the nuclear activity of IκBβ, the sustained expression of key pro-inflammatory target genes (COX-2, ET-1, IL1β) is significantly reduced ( 27 – 30 ). In contrast, by allowing IκBα/NFκB signaling to proceed, the expression of key antioxidant (MnSOD) and anti-inflammatory (A20) target genes that are not dependent upon nuclear IκBβ activity is unimpaired ( 28 ).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of IκBβ/NFκB signaling prevents LPS-induced IL1β expression without increasing apoptosis in the developing mouse lung

et al. 2017

Self Cite

View full text Add to dashboard Cite

Background The pro-inflammatory consequences of IL1β expression contribute to the pathogenesis of BPD. Selectively targeting LPS-induced IκBβ/NFκB signaling attenuates IL1β mRNA expression in macrophages. Whether targeting IκBβ/NFκB signaling affects anti-apoptotic gene expression, a known consequence of global LPS-induced NFκB inhibition, is unknown. Methods Macrophages (RAW 264.7, BMDM) were assessed for LPS-induced IL1β mRNA/protein expression, anti-apoptotic gene expression, cell viability (trypan blue exclusion) and activation of apoptosis (caspase-3 and PARP cleavage) following pharmacologic and genetic attenuation of IκBβ/NFκB signaling. Expression of IL1β and anti-apoptotic genes were assessed in endotoxemic newborn mice (P0) with intact (WT), absent (IκBβ KO) and attenuated (IκBβ overexpressing) IκBβ/NFκB signaling. Results In cultured macrophages, pharmacologic and genetic inhibition of LPS-induced IκBβ/NFκB signaling significantly attenuated IL1β mRNA and protein expression. Importantly, targeting IκBβ/NFκB signaling did not attenuate LPS-induced expression of anti-apoptotic genes or result in cell death. In endotoxemic neonatal mice, targeting LPS-induced IκBβ/NFκB signaling significantly attenuated pulmonary IL1β expression without affecting anti-apoptotic gene expression. Conclusion Targeting IκBβ/NFκB signaling prevents LPS-induced IL1β expression without inducing apoptosis in cultured macrophages and in the lungs of endotoxemic newborn mice. Inhibiting this pathway may prevent inflammatory injury without affecting the protective role of NFκB activity in the developing lung.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of IκBβ/NFκB signaling prevents LPS-induced IL1β expression without increasing apoptosis in the developing mouse lung

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…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%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Potential mechanisms and therapeutic strategies for LPS-associated female fertility decline

Qin,

Du,

et al. 2024

J Assist Reprod Genet

View full text Add to dashboard Cite

Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NFκB-Dependent Mechanism

Cited by 11 publications

References 40 publications

Inhibition of IκBβ/NFκB signaling prevents LPS-induced IL1β expression without increasing apoptosis in the developing mouse lung

Inhibition of IκBβ/NFκB signaling prevents LPS-induced IL1β expression without increasing apoptosis in the developing mouse lung

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

Potential mechanisms and therapeutic strategies for LPS-associated female fertility decline

Contact Info

Product

Resources

About