Endothelial Na+/H+ exchanger NHE1 participates in redox-sensitive leukocyte recruitment triggered by methylglyoxal

Qadri, Syed M.; Su, Yang; Cayabyab, Francisco S.; Liu, Lixin

doi:10.1186/s12933-014-0134-7

Cited by 11 publications

(12 citation statements)

References 83 publications

(85 reference statements)

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“…Previous studies in human T cells have suggested that addition of IL-2 to cultured cells could enhance pH i and NHE1 protein abundance, thus affecting cell proliferation, cytokine production, and apoptosis (51). It has been further proposed that pH i and NHE1 activity are modulated by glucocorticoids in a non-genomic fashion (49,(52)(53)(54)(55)(56). However, to which extent pH i and NHE activity govern Th9 cell development and function is incompletely understood.…”

Section: Cd4mentioning

confidence: 99%

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Singh

Zhou

Shi

et al. 2016

Journal of Biological Chemistry

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CD4؉ T helper 9 (Th9) cells are a newly discovered Th cell subset that produce the pleiotropic cytokine IL-9. Th9 cells can protect against tumors and provide resistance against helminth infections. Given their pivotal role in the adaptive immune system, understanding Th9 cell development and the regulation of IL-9 production could open novel immunotherapeutic opportunities. The Na ؉ /H ؉ exchanger 1 (NHE1; gene name Slc9␣1)) is critically important for regulating intracellular pH (pH i ), cell volume, migration, and cell survival. The pH i influences cytokine secretion, activities of membrane-associated enzymes, ion transport, and other effector signaling molecules such as ATP and Ca 2؉ levels. However, whether NHE1 regulates Th9 cell development or IL-9 secretion has not yet been defined. The present study explored the role of NHE1 in Th9 cell development and function. Th cell subsets were characterized by flow cytometry and pH i was measured using 2,7-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester (BCECF-AM) dye. NHE1 functional activity was estimated from the rate of realkalinization following an ammonium pulse. Surprisingly, in Th9 cells pH i and NHE1 activity were significantly higher than in all other Th cell subsets (Th1/Th2/Th17 and induced regulatory T cells (iTregs)). NHE1 transcript levels and protein abundance were significantly higher in Th9 cells than in other Th cell subsets. Inhibition of NHE1 by siRNA-NHE1 or with cariporide in Th9 cells down-regulated IL-9 and ATP production. NHE1 activity, Th9 cell development, and IL-9 production were further blunted by pharmacological inhibition of protein kinase Akt1/Akt2. Our findings reveal that Akt1/Akt2 control of NHE1 could be an important physiological regulator of Th9 cell differentiation, IL-9 secretion, and ATP production. CD4ϩ T cells participate in the regulation of the immune response during infections, autoimmunity, and cancer. CD4 ϩ T cells are an important and essential arm of the adaptive immune system (1). CD4 ϩ T cells can be divided into various subtypes based upon their cytokine secretion: T helper 1 (Th1) 4 cells produce IFN-␥ (1, 2), Th2 cells produce IL-4, IL-5, and IL-13 (3), Th17 cells produce IL-17 (4 -6), Th9 cells produce IL-9 (7-9), and suppressive regulatory T cells (Tregs) produce TGF-␤ and IL-10 (10). A great deal of experimental effort has been dedicated to decipher the development and function of various Th cell subsets. However, Th9 cell development and function remain incompletely understood.Th9 cells are a recently characterized Th cell subset recognized by their potent production of IL-9. Th9 cells play a pivotal role in health and disease. Th9 cells have been shown to exacerbate the airway allergic immune response by recruiting eosinophils and mast cells to the lungs, increasing mucus production, and production of serum IgE (11, 12). Th9 cells further contribute to the host-immune reaction against helminth infections and tumors (7, 13-23). The development and function of Th9 cells are regulated ...

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Section: Cd4mentioning

confidence: 99%

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Singh

Zhou

Shi

et al. 2016

Journal of Biological Chemistry

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“…In previous studies, the alteration of extracellular and intracellular pH affected the release of cytokines and the activation of signaling pathways (Dietl et al, 2010;Kellum et al, 2004;Riemann et al, 2016;Samuvel et al, 2009). Moreover, CD86 and CD54 expression is affected by acidic pH (Kong et al, 2013;Martínez et al, 2007; Qadri et al, 2014;Vermeulen et al, 2004). Therefore, we investigated CD86/CD54 expression with respect to medium pH and test chemicals.…”

Section: Discussionmentioning

confidence: 97%

“…NHE-1, H + -ATPases, and monocarboxylate-H + efflux cotransporters MCT1 and MCT4 regulate extra-and intracellular pH. In particular, cariporide, an inhibitor of NHE-1 activity, decreases CD54 expression in murine microvascular SVEC4-10EE2 endothelial cells (Qadri et al, 2014). In addition, in human chronic myeloid leukemia K562 cells, cariporide induces the suppression of protein kinase C-β (PKC-β) activation (Ma et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…According to a previous study, lactate enhances the release of IL-6 and IL-8 in human leukemic monocytes U937 and human monocytes (Samuvel et al, 2009). Moreover, acidic extracellular pH induces the augmentation of CD80 and CD86 expression and the production of IL-1β, IL-18, and TNF-α (Kong et al, 2013;Rajamäki et al, 2013). Therefore, the skin sensitization markers are affected by acidic extracellular pH.…”

Section: Introductionmentioning

confidence: 92%

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Acidic conditions induce the suppression of CD86 and CD54 expression in THP-1 cells

et al. 2018

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To evaluate the sensitization potential of chemicals in cosmetics, using non-animal methods, a number of in vitro safety tests have been designed. Current assays are based on the expression of cell surface markers, such as CD86 and CD54, which are associated with the activation of dendritic cells, in skin sensitization tests. However, these markers are influenced by culture conditions through activating danger signals. In this study, we investigated the relationship between extracellular pH and the expression of the skin sensitization test human cell line activation test (h-CLAT) markers CD86 and CD54. We measured expression levels after THP-1 cells were exposed to representative contact allergens, i.e., 2,4-dinitrochlorobenzene and imidazolidinyl urea, under acidic conditions. These conditions were set by exposure to hydrochloric acid, lactic acid, and citric acid. An acidic extracellular pH (6-7) suppressed the augmentation of CD86 and CD54 levels by the sensitizer. Additionally, when the CD86/CD54 expression levels were suppressed, a reduction in the intracellular pH was confirmed. Furthermore, we observed that Na/H exchanger 1 (NHE-1), a protein that contributes to the regulation of extracellular/intracellular pH, is involved in CD86 and CD54 expression. These findings suggest that the extracellular/intracellular pH has substantial effects on in vitro skin sensitization markers and should be considered in evaluations of the safety of mixtures and commercial products in the future.

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“…Indeed, MG‐induced DNA damage has been shown to be associated with increased numbers of aberrant crypt foci in the colon of thiamine‐deficient rats . MG also induces AGE formation , inflammation , insulin resistance (via carbonylation of insulin or impairment of the insulin signaling pathway ), and angiogenesis (via targeting vascular endothelial growth factor receptor dependent signaling pathways ). Each of these effects may increase cancer risk, enhance cancer progression, or worsen prognosis in cancer patients with obesity and/or diabetes , even though MG may impair the activity of the proteasome, which plays a key role in cancer cell survival under hyperglycemic conditions .…”

Section: Major Age Precursors Dicarbonyls In Cancer Biologymentioning

confidence: 99%

Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: An emerging biological factor in cancer onset and progression

Lin

et al. 2016

Molecular Nutrition Food Res

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In recent years, glycative stress from exogenous or endogenous advanced glycation end products (AGEs) and highly reactive dicarbonyls has gained great attention for its putative effects on cancer development. AGEs are a group of compounds formed from the complex chemical reaction of reducing sugars with compounds containing an amino group. AGEs bind to and activate the receptor for AGEs (RAGE), which is a predominant modulator of inflammation-associated cancer, and AGEs induce reactive oxygen species that are an important regulator of the hallmarks of cancer. Dicarbonyls, which are formed during glycolysis, lipid oxidation, or protein degradation, include glyoxal, methylglyoxal, and 3-deoxyglucosone and are regarded as major precursors of AGEs. These dicarbonyls not only fuel the AGE pool in living organisms but also evoke carbonyl stress, which may contribute to the carbonylative damage of carbohydrates, lipids, proteins, or DNA. Carbonylative damage then leads to many lesions, some of which are implicated in the pathogenesis of cancer. In this review, studies regarding the effects of AGEs and dicarbonyls on cancer onset or progression are systematically discussed, and the utilization of AGE inhibitors and dicarbonyl scavengers in cancer therapy are noted.

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Endothelial Na+/H+ exchanger NHE1 participates in redox-sensitive leukocyte recruitment triggered by methylglyoxal

Cited by 11 publications

References 83 publications

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Acidic conditions induce the suppression of CD86 and CD54 expression in THP-1 cells

Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: An emerging biological factor in cancer onset and progression

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