Toll-Like Receptor 1/2 Stimulation Induces Elevated Interleukin-8 Secretion in Polymorphonuclear Leukocytes Isolated from Preterm and Term Newborn Infants

Thornton, Nathan L.; Yost, Christian C.

doi:10.1159/000330567

Cited by 17 publications

(13 citation statements)

References 66 publications

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“…This observation seems to contradict our finding regarding reduced cytokine responses of monocytes to LPS in vitro. The discrepancy can be explained by the fact that the plasma cytokines in these newborns also encompass contributions from other blood cells (12,32) and other tissues (31).…”

Section: Postnatal Development Of Tlr In Pretermsmentioning

confidence: 96%

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Development of monocyte Toll-like receptor 2 and Toll-like receptor 4 in preterm newborns during the first few months of life

et al. 2013

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Background: Although the immaturity of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) at birth in preterm newborns is known, their development during the first few months of life remains unclear. Methods: Blood monocytes of preterm newborns (gestational age: 24-36 wk) were obtained every 2 wk when possible in order to perform serial measurements of TLR2 and TLR4 surface expression, as well as lipopolysaccharide (LPS)-induced cytokine production. Measurements using monocytes from term newborns and adults were also performed. results: The monocytes of preterm newborns obtained at birth displayed reduced surface expression of TLR2 and TLR4, and diminished responses of tumor necrosis factor-α (TNF-α) and interleukin (IL)-8 to LPS stimulation. Regardless of gestational age, monocyte expression of TLR2 and TLR4 in preterm newborns increased rapidly within the first 2 wk after birth, quickly reaching those of term newborns. These increases continued for the following 4-6 wk, although the increase began to plateau. By contrast, LPS-induced production of TNF-α and IL-8 did not elevate over this period in preterm newborns. conclusion: The blood monocytes of preterm newborns display rapid increase in TLR2 and TLR4 expression during the first few months of life, whereas LPS-induced cytokine production functionality did not improve in parallel.

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Section: Postnatal Development Of Tlr In Pretermsmentioning

confidence: 96%

“…Clinical (8)(9)(10)(11)(12) and animal studies (13)(14)(15) indeed have shown reduced expression of TLR2 and TLR4, as well as diminished function in cytokine production induced by their agonists at birth, in preterm newborns. However, deficiencies in the TLR system at birth do not necessarily mean that it does not improve during the early postnatal period.…”

mentioning

confidence: 99%

Development of monocyte Toll-like receptor 2 and Toll-like receptor 4 in preterm newborns during the first few months of life

et al. 2013

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“…Despite this weak anti-inflammatory capability, very preterm newborns appear to be capable of a more vigorous systemic inflammatory response than gestationally-older newborns (47,48). The result is a propensity to a pro-inflammatory imbalance of proteins that is not readily eliminated.…”

Section: Mechanismsmentioning

confidence: 99%

Intermittent or sustained systemic inflammation and the preterm brain

2013

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Exposure to perinatal infection and inflammation is associated with an increased risk for neonatal brain damage and developmental disabilities. In this integrated mechanism review, we discuss evidence in support of the contention that the preterm newborn is capable of intermittent or sustained systemic inflammation (ISSI), which appears to contribute more to adverse neurodevelopmental outcomes in preterm infants than does shorter duration inflammation.

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“…In previous experiments, we have shown that IL-8 protein synthesis is regulated by transcription in activated human PMNs. 13,27 We examined the sequence of the 5Ј-UTR of the HIF-1␣ transcript identified by RNA-seq in PMNs (Figure 2A) and found that it exhibited substantial complexity with a base pair length of 339 and estimated secondary structure energy of Ϫ182.4 kcal/mol ( Figure 2B). These features are characteristic of transcripts whose translation is controlled by mTOR in nonimmune cells 28 and in human PMNs.…”

Section: Mtor Is a Posttranscriptional Regulator Of Hif-1␣ Protein Exmentioning

confidence: 99%

Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 α

McInturff

Cody

Elliott

et al. 2012

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Neutrophils are highly specialized innate immune effector cells that evolved for antimicrobial host defense. In response to inflammatory stimuli and pathogens, they form neutrophil extracellular traps (NETs), which capture and kill extracellular microbes. Deficient NET formation predisposes humans to severe infection, but, paradoxically, dysregulated NET formation contributes to inflammatory vascular injury and tissue damage. The molecular pathways and signaling mechanisms that control NET formation remain largely uncharacterized. Using primary human neutrophils and genetically manipulated myeloid leukocytes differentiated to surrogate neutrophils, we found that mammalian target of rapamycin ( IntroductionNeutrophils (polymorphonuclear leukocytes, PMNs) are key effector cells in infection, inflammation, and tissue injury. 1 Formation of neutrophil extracellular traps (NETs), first identified with human PMNs, is a function of neutrophils. 2 NETs are complex lattices of decondensed chromatin that trap and kill bacteria, fungi, and some parasites by exposing them to high concentrations of NETassociated microbicidal factors. 3,4 Rapidly evolving studies indicate that NETs effect extracellular microbial killing while limiting the spread of pathogens in vivo. 3,5 The intracellular signaling pathways that regulate NET formation by PMNs remain largely unknown. There is evidence that generation of reactive oxygen species (ROS) is a key event. 4,6 Nevertheless, we showed in primary human PMNs that NET formation requires signaling events and regulatory pathways in addition to ROS generation. 4 Consistent with our results, subsequent studies in human HL-60 myeloid leukocytes and genetically altered mice indicate that activity of peptidylarginine deiminase 4, an enzyme responsible for chromatin decondensation, is also required. 5,7 Recent observations further suggest that NET formation requires enzymatic activity of neutrophil elastase (NE) and myeloperoxidase to initiate degradation of core histones that lead to chromatin decondensation before plasma membrane rupture. 8 Furthermore, ROS generation and NET formation can be dissociated under some conditions. 9,10 Thus, molecular regulation of NET formation is complex and may involve multiple signaling pathways and effector events, depending on the neutrophil agonists and inflammatory context.The mammalian target of rapamycin (mTOR) is a highly conserved PI3K-like serine/threonine kinase with functional homologs found in all studied eukaryotic organisms. 11 mTOR integrates nutrient, energy, oxygen sensing, and mitogenic input signals. 12 We found that mTOR also responds to inflammatory signals and mediates a previously unrecognized pathway of posttranscriptional gene regulation in human PMNs. 13 These results identified a new mechanism by which mTOR can regulate innate, as well as, adaptive, immune responses. Immunoregulatory activities of mTOR are now increasingly recognized. 14 Recent observations indicate that hypoxia inducible factor 1␣ (HIF-1␣), the regulated subunit of ...

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Toll-Like Receptor 1/2 Stimulation Induces Elevated Interleukin-8 Secretion in Polymorphonuclear Leukocytes Isolated from Preterm and Term Newborn Infants

Cited by 17 publications

References 66 publications

Development of monocyte Toll-like receptor 2 and Toll-like receptor 4 in preterm newborns during the first few months of life

Development of monocyte Toll-like receptor 2 and Toll-like receptor 4 in preterm newborns during the first few months of life

Intermittent or sustained systemic inflammation and the preterm brain

Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 α

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