Lipopolysaccharide induces 5-lipoxygenase-activating protein gene expression in THP-1 cells via a NF-κB and C/EBP-mediated mechanism

Serio, Kenneth J.; Reddy, Krishna; Bigby, Timothy D.

doi:10.1152/ajpcell.00296.2004

Cited by 45 publications

(32 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results indicated that hypoxia mediated signaling leading to FLAP expression involved HIF-1a and NF-kB. LPS-mediated FLAP expression in THP-1 cells was previously shown to require both NF-kB and C/EBP for FLAP promoter activation (25).…”

Section: Discussionsupporting

confidence: 52%

“…PTEN overexpression and PI3K dominant negative plasmids were generous gifts from Dr. Debbie Johnson (Keck School of Medicine, University of Southern California, Los Angeles, CA). The 23368FLAP-pGL3 full-length FLAP promoter constructs and the deletion constructs (2965FLAP-pGL3, 2371FLAP-pGL3, and 2134FLAP-pGL3) were generously provided by Dr. Timothy Bigby (25) (Veterans' Administration Hospital San Diego, La Jolla, CA). The pcDNA3-5 LO vector was kindly provided by Dr. Colin Funk (Queen's University, Kingston, Ontario, Canada).…”

Section: Reagentsmentioning

confidence: 99%

“…4A, contains four putative consensus HIF-1a binding (RCGTG) elements (2635 to 2632 bp, 2517 to 2514 bp, 2264 to 2261 bp, and 2170 to 2167 bp), relative to transcriptional start site, along with a NF-kB site (located at 243 to 2 34 bp) and a C/EBP consensus binding site (located at 236 to 2 28 bp and 225 to 212 bp). Bigby and his coworkers (25) have shown that LPS-induced FLAP expression in THP-1 cells requires the binding of both NF-kB and C/EBP to the FLAP promoter. As shown in Fig.…”

Section: Hypoxia-mediated Upregulation Of the Flap Gene Requires Proxmentioning

confidence: 99%

See 2 more Smart Citations

Hypoxia-Mediated Expression of 5-Lipoxygenase–Activating Protein Involves HIF-1α and NF-κB and MicroRNAs 135a and 199a-5p

Gonsalves

Kalra

2010

The Journal of Immunology

View full text Add to dashboard Cite

Hypoxia occurs in a number of pathological states, such as pulmonary, hematological, and cardiovascular disorders. In this study, we examined the molecular mechanism by which hypoxia contributes to increased leukotriene formation. Our studies showed hypoxia augmented the expression of 5-lipoxygenase activating protein (FLAP), a key enzyme in leukotriene formation, in both human pulmonary microvascular endothelial cells and a transformed human brain endothelial cell line. Hypoxia-induced FLAP mRNA expression involved activation of NADPH-oxidase, PI-3 kinase, mitogen-activated protein kinase, NF-κB, and hypoxia-inducible factor (HIF)-1α. Hypoxia-induced FLAP promoter activity was attenuated on mutation of hypoxia-response elements (HREs) and NF-κB binding motif in the FLAP promoter. Hypoxia also augmented binding of HIF-1α to HREs in FLAP promoter as demonstrated by EMSA with nuclear extracts. Furthermore, chromain immunoprecipitation analysis showed HIF-1α bound to HREs in native chromatin obtained from hypoxia-treated cells. Next, we examined the role of HIF-1α regulated microRNAs on FLAP expression. Our studies showed decreased expression of miR-135a and miR-199a-5p in response to hypoxia. However, overexpression of anti–miR-135a and anti–miR-199a-5p oligonucleotides led to a several fold increased FLAP mRNA and protein expression. These studies demonstrate for the first time that hypoxia-mediated FLAP expression is regulated by HREs and NF-κB site in its promoter, and negatively regulated by miR-135a and miR-199a-5p, which target the 3′-UTR of FLAP mRNA. An understanding of these regulatory pathways provides new avenues to ameliorate leukotriene formation and hence reactive airway disease, and inflammation in individuals who have sickle cell disease.

show abstract

Section: Discussionsupporting

confidence: 52%

Section: Reagentsmentioning

confidence: 99%

Section: Hypoxia-mediated Upregulation Of the Flap Gene Requires Proxmentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia-Mediated Expression of 5-Lipoxygenase–Activating Protein Involves HIF-1α and NF-κB and MicroRNAs 135a and 199a-5p

Gonsalves

Kalra

2010

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…24 As shown in Figure 5C, PlGF increased FLAP promoter activity by 5-fold (designated as 100% compared with the promoterless pGL3 vector). Analysis of serial deletion constructs of FLAP promoter showed that Ϫ371/ϩ12-bp region of the FLAP promoter had similar activity as the full-length FLAP promoter, but Ϫ134/ϩ12-bp promoter construct (lacking the HRE sites) showed reduced activity in response to PlGF ( Figure 5C).…”

Section: Plgf-mediated Flap Promoter Activity Requires Hre But Not Nfmentioning

confidence: 84%

Placenta growth factor induces 5-lipoxygenase–activating protein to increase leukotriene formation in sickle cell disease

Patel

Gonsalves

Yang

et al. 2009

Blood

View full text Add to dashboard Cite

IntroductionInflammation is increasingly recognized as central to the pathophysiology of sickle cell disease (SCD) and is manifest as leukocytosis, elevated levels of inflammatory cytokines, and activation of neutrophils, monocytes, and endothelial cells. [1][2][3][4] It is present at steady state and is strongly associated with acute painful events, acute chest, and early mortality. 5,6 Current evidence strongly suggests that inflammation contributes to the endothelial cell dysfunction, potentiates vasoocclusion, and may also give rise to the airway hyperreactivity (AH) that often accompanies SCD. [7][8][9][10] Also intriguing is the spectrum of lung disease seen in this patient population, which spans from an increased incidence of AH and obstructive lung disease in children, [11][12][13] to restrictive lung disease and pulmonary vascular remodeling, which is associated with pulmonary hypertension in adults. [14][15][16][17][18] Leukotrienes (LT) mediate both inflammation and AH. 19-22 5-Lipoxygenase (5-LO) and its activating partner, 5-lipoxygenase activating protein (FLAP), catalyze the production of LT from arachidonic acid (AA) by generating 5-hydroperoxyeicostatraenoic acid (5-HPETE) and leukotriene A 4 (LTA 4 ). LTA 4 is the pivotal intermediate from which other LTs (ie, LTB 4 and cysteinyl LT [CysLT], LTC 4 , LTD 4 , and LTE 4 ) are formed. 20 LTB 4 is one of the most potent chemoattractant for neutrophils, eosinophils, and mediator of inflammation. CysLT, on the other hand, are potent bronchoconstrictors that play an important role in edema, inflammation, and mucus secretion in asthma and were previously termed "slow releasing substances." 23 LT play an important role in the pathogenesis of inflammatory disorders, specifically asthma, rheumatoid arthritis, and inflammatory bowel disease. [19][20][21] Studies by Bigby and coworkers 24,25 have shown that both tumor necrosis factor-␣ (TNF-␣) and lipopolysaccharide (LPS) induce the expression of FLAP in THP-1 cells. These studies showed the importance of nuclear factor-B (NF-B) and CCAAT/enhancer binding protein (C/EBP) transcription factors in the LPS-mediated FLAP expression. 24 LTB 4 levels are higher in SCD patients at steady state, which are further increased in vasoocclusive pain crises (VOC) and acute chest syndrome (ACS). 26 Very recently, increased LTE 4 has been observed in patients with SCD, which is associated with a higher incidence of pain. 27 However, less is understood about how LTs are increased in SCD at the molecular level.Placenta growth factor (PlGF) is an angiogenic growth factor with similar effects on endothelium as vascular endothelial growth factor (VEGF) and is primarily expressed by placental trophoblasts. [28][29][30] More recently, we and others show that erythroid cells, but not other hematopoietic cells, produce PlGF, and its expression is high in SCD and thalassemia. 31,32 VEGFR1 is its cognate receptor and is expressed on endothelial cells, alveolar epithelial cells, mast cells, and monocytes. We have previously shown that...

show abstract

“…CS and LPS alone could activate NF-kB in macrophages (20,21) and, more importantly, CS exposure in vivo increased the NFkB-activating response to LPS (22). In addition, NF-kB is reported to be downstream of phosphatidylinositol 3-kinase (PI3K)/Akt (23,24).…”

mentioning

confidence: 99%

Cigarette Smoke Synergizes Lipopolysaccharide-Induced InterIeukin-1β and Tumor Necrosis Factor–α Secretion from Macrophages via Substance P–Mediated Nuclear Factor–κB Activation

Xu²,

Lin³

2011

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

A recent study has indicated that alveolar macrophages from smokers incubated with lipopolysaccharide (LPS) secrete much more IL-1b and TNF-a than those from healthy nonsmokers, but the mechanisms underlying this augmented secretion by cigarette smoke (CS) remain unknown. CS and LPS reportedly promote macrophages' secreting substance P (SP) that could up-regulate these cytokines' secretion from macrophages by acting on neurokinin 1 receptor (NK1R). Moreover, NF-kB from macrophages participates in NK1R intracellular signaling and synthesis of these cytokines. The present in vitro study was undertaken to examine whether CS is able to synergize these cytokines' response to LPS in macrophages, and if so, whether an amplified SP secretion is responsible for this synergistic cytokines' response via a NK1R-driven NF-kB pathway. THP-1-derived and MH-S macrophages were exposed to control medium and CS condensate (CSC) without or with LPS. We found that LPS, CSC, and CSC1LPS significantly increased IL1b, TNF-a, and SP secretion and that SP secretion markedly preceded cytokines' secretion. CSC1LPS-induced responses were markedly greater than the sum of the responses to CSC and LPS alone, suggesting a synergistic effect. Blocking NK1R reduced the responses of IL-1b, TNF-a, and NF-kB activation to CSC1LPS by 41, 40, and 46%, respectively. NF-kB inhibitors decreased the CSC1LPS-induced cytokines' responses by 70%. Our findings suggest that CS amplifies the LPS-induced macrophages' secretion of IL-1b and TNF-a through synergizing SP secretion, which activates NF-kB via binding with NK1R.Keywords: cytokines; infection; emphysema; signal pathway of NF-kB IL-1b and TNF-a are important cytokines participating in the pathogenesis of multiple pulmonary diseases, such as pulmonary infection, fibrosis, cancer, and emphysema (1-4). For example, cigarette smoke (CS)-induced emphysema was diminished up to 83% in mice that were null of receptors for IL1b and TNF-a (4). Macrophages are one of the important sources these cytokines (5), especially during infection (6). It was reported that pulmonary infection induced by intratracheal instillation of lipopolysaccharide (LPS) substantially promoted cytokine secretion from macrophages (7). A recent study has further indicated that alveolar macrophages from smokers incubated with LPS secrete much more IL-1b and TNF-a than those from healthy nonsmokers (8). This finding, along with a higher secretion of these cytokines in smokers with pulmonary infection than in those without infection (6), implies a synergistic effect of CS exposure on macrophage secretion of these cytokines induced by LPS. However, the exact mechanisms underlying this CS augmented effect on cytokine secretion have not been investigated.There is evidence demonstrating synergistic impacts of CS on the receptors' expression or mucin secretion. We have observed that alveolar macrophages from mice exposed to CS express more neurokinin 1 receptors (NK1R) in response to substance P (SP) compared with those from control mice (9). Moreo...

show abstract

Lipopolysaccharide induces 5-lipoxygenase-activating protein gene expression in THP-1 cells via a NF-κB and C/EBP-mediated mechanism

Cited by 45 publications

References 50 publications

Hypoxia-Mediated Expression of 5-Lipoxygenase–Activating Protein Involves HIF-1α and NF-κB and MicroRNAs 135a and 199a-5p

Hypoxia-Mediated Expression of 5-Lipoxygenase–Activating Protein Involves HIF-1α and NF-κB and MicroRNAs 135a and 199a-5p

Placenta growth factor induces 5-lipoxygenase–activating protein to increase leukotriene formation in sickle cell disease

Cigarette Smoke Synergizes Lipopolysaccharide-Induced InterIeukin-1β and Tumor Necrosis Factor–α Secretion from Macrophages via Substance P–Mediated Nuclear Factor–κB Activation

Contact Info

Product

Resources

About