Involvement of mitogen-activated protein kinases and NFκB in LPS-induced CD40 expression on human monocytic cells

Wu, Weidong; Alexis, Neil E.; Chen, Xian; Bromberg, Philip A.; Peden, David B.

doi:10.1016/j.taap.2007.12.002

Cited by 25 publications

(9 citation statements)

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“…We subsequently studied the specific roles of TLR4 and CD14 in LPSinduced release of CXCL8, TNF-␣, and IL-10 from PBLs of neonates and adults. Treatment with anti-TLR4 resulted in partial inhibition of the LPS-induced CXCL8 release from PBLs of preterm and full-term neonates and adults (38,21, and 14%, Figure 1. Increased TLR4 and CD14 surface expression in monocytes from neonates.…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether the neonatal PBL responses observed after LPS stimulation were, at least partly, induced by monocytes, we performed a similar set of experiments using the human monocytic THP-1 cell line. THP-1 monocytes have been extensively used for the study of LPS-induced TLR4 signaling (21,22,23). Anti-TLR4 treatment partially inhibited (17%) the LPS-induced CXCL8 release, whereas CD14 blockade resulted in a 4-fold greater inhibition (76%) of CXCL8 release, compared with anti-TLR4 (Fig.…”

Section: Effects Of Tlr4 and Cd14 Blockade On Lps-induced Responses Imentioning

confidence: 96%

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Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory Responses of Neonates

et al. 2009

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During infections, pathogens bind to toll-like receptor (TLR)4 and CD14 receptors and induce cytokine release, leading to inflammation. Here, we investigated TLR4 and CD14 expression on peripheral blood leukocytes (PBLs) and their roles in lipopolysaccharide (LPS)-induced cytokine and chemokine release. Full-term and preterm neonates and adults were studied. PBLs were pretreated with anti-TLR4 -and anti-CD14 -blocking antibodies and stimulated with LPS. Cytokine and chemokine levels were measured in supernatants. TLR4, CD14 expression, and LPS-induced CXCL8 release were higher in neonates, possibly contributing to aberrant inflammation. TLR4 blockade resulted in approximately 3-fold greater suppression of LPS-induced CXCL8 release in preterm neonates (38%) than in adults (14%). CD14 blockade (ϳ80%) in neonates induced approximately 3-fold greater inhibition of CXCL8 release, compared with anti-TLR4 (ϳ30%). Anti-TLR4 partly (50 -60%) inhibited IL-10 and TNF-␣, whereas anti-CD14 completely suppressed their release. Our findings reveal that neonates depend more on TLR4 for CXCL8 release. Furthermore, neonatal LPS-induced CXCL8 release, apart from TLR4/CD14-mediated signaling, is regulated by LPS interactions with other TLRs and/or immune receptors. IL-10 and TNF-␣ release depends on LPS binding not only to CD14/TLR4 but also to CD14 associated with another TLR. Our findings reveal the contribution of TLR4 and CD14 in neonatal cytokine and chemokine release and could aid in design of antagonists to prevent harmful inflammation. (Pediatr Res 66: 179-184, 2009) N eonates are highly susceptible to Gram-negative bacteria that induce high morbidity and mortality. The principal pathogenic agent involved in neonatal sepsis induced by Gramnegative bacteria is endotoxin lipopolysaccharide (LPS), an essential component of their surface. Defense against pathogens is offered by immune cells, such as granulocytes, monocytes, and dendritic cells (DCs), which express pattern-recognition receptors (PRRs) that recognize specific structures present on microorganisms, termed pathogen-associated molecular patterns (PAMPs) (1). Binding of PAMPs to PRRs triggers antimicrobial responses to combat the infection (1,2).LPS is one of the best characterized PAMPs that binds to the CD14/toll-like receptor (TLR)4/MD2 complex of PRRs and activates intracellular signaling (3). CD14 binds to LPS but lacks an intracellular component and is, thus, incapable of signaling. MD2 is a molecule necessary for LPS recognition by TLR4, which also cannot mediate signaling. TLR4, upon LPS binding, leads to intracellular activation of mitogenactivated protein kinase and nuclear factor-B that mediate the transcription of proinflammatory cytokine and chemokine genes (4). TLR4 signaling also activates DCs that subsequently present pathogenic peptides to T lymphocytes and, thus, stimulate T-cell-mediated immunity (5).The specific roles of TLR4 and CD14 in LPS-induced inflammatory responses by neonatal leukocytes remain not clearly defined. Studies in neona...

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Section: Resultsmentioning

confidence: 99%

Section: Effects Of Tlr4 and Cd14 Blockade On Lps-induced Responses Imentioning

confidence: 96%

Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory Responses of Neonates

et al. 2009

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“…MAPKs (ERK1/2, p38␣, and JNK) cooperate with the TLR and JAK2 signaling pathways, which are triggered by various extracellular stimuli (36,37). In addition, pathogen-associated PI3K activation has been demonstrated to be necessary for induction of phagocytosis (38).…”

Section: Resultsmentioning

confidence: 99%

Toll-Like Receptor 4-Linked Janus Kinase 2 Signaling Contributes to Internalization of Brucella abortus by Macrophages

Lee

Kim

et al. 2013

Infect Immun

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e Brucella abortus is an intracellular pathogen that uses a crafty strategy to invade and proliferate within host cells, but the distinct signaling pathways associated with phagocytic mechanisms of B. abortus remain unclear. The present study was performed to test the hypothesis that Toll-like receptor 4 (TLR4)-linked signaling interacting with Janus kinase 2 (JAK2) plays an essential role in B. abortus phagocytosis by macrophages. The effects of TLR4-JAK2 signaling on B. abortus phagocytosis in murine macrophage RAW 264.7 cells were observed through an infection assay and confocal microscopy. We determined that the uptake of B. abortus was negatively affected by the dysfunction of TLR4 and JAK2. F-actin polymerization detected by flow cytometry and F-actin assay was amplified for B. abortus entry, whereas that event was attenuated by the disruption of TLR4 and JAK2. Importantly, JAK2 phosphorylation and actin skeleton reorganization were suppressed immediately after B. abortus infection in bone marrow-derived macrophages (BMDMs) from TLR4 ؊/؊ mice, showing the cooperation of JAK2 with TLR4. Furthermore, small GTPase Cdc42 participated in the intermediate pathway of TLR4-JAK2 signaling on B. abortus phagocytosis. Consequently, TLR4-associated JAK2 activation in the early cellular signaling events plays a pivotal role in B. abortus-induced phagocytic processes in macrophages, implying the pathogenic significance of JAK2-mediated entry. Here, we elucidate that this specific phagocytic mechanism of B. abortus might provide achievable strategies for inhibiting B. abortus invasion.

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“…The alteration of cytokine gene expression in THP-1 cells by pure trichothecenes (e.g., deoxynivalenol) and extract of Aspergillus fumigatus has been reported to be mediated by Erk1/2, p38 mitogen-activated kinase (Shalit et al, 2006), PKC (Ma et al, 2001;O'Sullivan et al, 2008), and the Toll-like receptor 4 (Wu et al, 2008). Others have reported the involvement of Bruton's tyrosine kinase in the cytosol (Jefferies et al, 2003), which, in turn, activates downstream transcriptional factors NFjB, SP1, STAT-1, and AP-1 in the cell nuclei (Hall et al, 1999;Ma et al, 2001;Chen et al, 2002;Jefferies et al, 2003).…”

Section: Mechanisms Of Trichothecene-induced Responsesmentioning

confidence: 99%

Inflammatory cytokine gene expression in THP‐1 cells exposed to Stachybotrys chartarum and Aspergillus versicolor

Pei

Gunsch

2011

Environmental Toxicology

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Very little is known about the mechanisms which occur in human cells upon exposure to fungi as well as their mycotoxins. A better understanding of toxin-regulated gene expression would be helpful to identify safe levels of exposure and could eventually be the basis for establishing guidelines for remediation scenarios following a water intrusion event. In this research, cytokine mRNA expression patterns were investigated in the human monocytic THP-1 cell line exposed to fungal extracts of various fragment sizes obtained from Stachybotrys chartarum RTI 5802 and/or Aspergillus versicolor RTI 3843, two common and well studied mycotoxin producing fungi. Cytokine mRNA expression was generally upregulated 2 to 10 times following a 24-hour exposure to fungal extracts. Expression of the proinflammatory interleukin-1β (IL-1β), Interleukin-8 (IL-8) and tumor necrosis factor-α (TNFα) genes increased while the anti-inflammatory gene Interleukin-10 (IL-10) also increased albeit at very low level, suggesting that negative feedback regulation mechanism of production of pro-inflammatory cytokines initiated upon 24 hours of incubation. In addition, submicron size extracts of A. versicolor caused significant death of THP-1 cells whereas extracts of S. chartarum caused no cell death while the mixture of the two fungi had an intermediate effect. There was no general correlation between gene expression and fragment sizes, which suggests that all submicron fragments may contribute to inflammatory response.

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Involvement of mitogen-activated protein kinases and NFκB in LPS-induced CD40 expression on human monocytic cells

Cited by 25 publications

References 56 publications

Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory Responses of Neonates

Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory Responses of Neonates

Toll-Like Receptor 4-Linked Janus Kinase 2 Signaling Contributes to Internalization of Brucella abortus by Macrophages

Inflammatory cytokine gene expression in THP‐1 cells exposed to Stachybotrys chartarum and Aspergillus versicolor

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