Contribution of Extracellular Signal-Regulated Kinase to UTP-Induced Interleukin-6 Biosynthesis in HaCaT Keratinocytes

Kobayashi, Daisaku; Ohkubo, Satoko; Nakahata, Norimichi

doi:10.1254/jphs.fp0060669

Cited by 16 publications

(12 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2C) indicated that 2-APB could prevent MeHg-induced IL-6 release. This observation was consistent with earlier reports that showed 2-APB could inhibit calcium signaling-induced IL-6 mRNA synthesis [17] and IL-6 protein production [15]. There is a possibility that calcium signaling was required for MeHg-induced IL-6 release in this experimental system.…”

Section: Discussionsupporting

confidence: 93%

Methylmercury-induced IL-6 release requires phospholipase C activities

Chang

2011

Neuroscience Letters

View full text Add to dashboard Cite

Methylmercury (MeHg) is a neurotoxin capable of causing severe damage to the CNS, especially in the developing fetus. Glia in the CNS release a number of cytokines that are important for proper CNS development and function. We reported earlier that MeHg could induce interleukin-6 (IL-6) release in primary mouse glia. This finding is significant considering previous reports indicating that sustained IL-6 exposure could be detrimental to cerebellar granule neurons, one of the major cellular targets of MeHg cytotoxicity. By using pharmacological antagonists against phophatidycholine- and phosphoinositol-specific phospholipase C, the current study indicated that phospholipase C activity was necessary for MeHg-induced IL-6 release. Results from pharmacological antagonists further suggested that the calcium signaling initiated by phospholipase C appeared essential for this event. In contrast, protein kinase C activity did not appear to be important. Even though mitogen-activated protein kinases were important for IL-6 release in some experimental systems, these enzymes did not appear to be required for MeHg-induced IL-6 release in glia. Based on these data and those reported by us and others, there is a possibility that MeHg-induced phospholipase C activation initiates a calcium signaling that causes phospholipase A2 activation. This, in turn, leads to arachidonic acid and lysophosphatidyl choline generation, both of which are potent inducers for IL-6 release.

show abstract

Section: Discussionsupporting

confidence: 93%

Methylmercury-induced IL-6 release requires phospholipase C activities

Chang

2011

Neuroscience Letters

View full text Add to dashboard Cite

show abstract

“…In addition to adenine nucleotide receptors, mRNAs of uracil nucleotide receptors were also detected in HaCaT cells, including P2Y2, P2Y4, and P2Y6 (Figure 3C). Uridine-5'-triphosphate (UTP) has been shown to stimulate interleukin-6 production in HaCaT keratinocytes and modulate keratinocyte migration via P2Y receptor activation [15], [23], [26], [57], [58]. Our preliminary results confirm that both UTP and uridine diphosphate (UDP) can elicit [Ca 2+ ] i increase, suggesting functional uracil nucleotide receptors are expressed in HaCaT keratinocytes (unpublished data).…”

Section: Discussionsupporting

confidence: 67%

“…In the epidermis, P2 receptors are involved in regulating proliferation, differentiation, and apoptosis [19]–[21]. Nucleotide triphosphates and P2Y receptor activation protects HaCaT cells from H 2 O 2 -induced cell damage [22] and inhibits keratinocyte spreading and migration [23], and correlates with thermotransduction in skin [11], chemokine expression in human keratinocytes [24], interleukin (IL)-6 expression and release in normal human epidermal keratinocytes [25], and IL-6 production via intracellular calcium elevation [15], [26]. Human keratinocytes secrete nucleotide triphosphate and express multiple nucleotide receptors that correlate with cell proliferation, differentiation, apoptosis, and migration [27], [28].…”

Section: Introductionmentioning

confidence: 99%

Ecto-Nucleoside Triphosphate Diphosphohydrolase 2 Modulates Local ATP-Induced Calcium Signaling in Human HaCaT Keratinocytes

Ho¹,

Yang

Lin³

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

Keratinocytes are the major building blocks of the human epidermis. In many physiological and pathophysiological conditions, keratinocytes release adenosine triphosphate (ATP) as an autocrine/paracrine mediator that regulates cell proliferation, differentiation, and migration. ATP receptors have been identified in various epidermal cell types; therefore, extracellular ATP homeostasis likely determines its long-term, trophic effects on skin health. We investigated the possibility that human keratinocytes express surface-located enzymes that modulate ATP concentration, as well as the corresponding receptor activation, in the pericellular microenvironment. We observed that the human keratinocyte cell line HaCaT released ATP and hydrolyzed extracellular ATP. Interestingly, ATP hydrolysis resulted in adenosine diphosphate (ADP) accumulation in the extracellular space. Pharmacological inhibition by ARL 67156 or gene silencing of the endogenous ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) isoform 2 resulted in a 25% reduction in both ATP hydrolysis and ADP formation. Using intracellular calcium as a reporter, we found that although NTPDase2 hydrolyzed ATP and generated sustainable ADP levels, only ATP contributed to increased intracellular calcium via P2Y2 receptor activation. Furthermore, knocking down NTPDase2 potentiated the nanomolar ATP-induced intracellular calcium increase, suggesting that NTPDase2 globally attenuates nucleotide concentration in the pericellular microenvironment as well as locally shields receptors in the vicinity from being activated by extracellular ATP. Our findings reveal an important role of human keratinocyte NTPDase2 in modulating nucleotide signaling in the extracellular milieu of human epidermis.

show abstract

“…Nonadenine NTPs and NDPs such as UTP and UDP are agonists for a number of P2Y receptors and in some cases have higher affinity for these receptors than ATP (20). UTP has also been shown to stimulate expression and release of the proinflammatory cytokine IL-6 (48,89). Furthermore, UDP, a selective P2Y6 agonist, stimulates production and release of IL-8 and tumor necrosis factor alpha in human monocytic cell lines (37,156).…”

Section: Nonadenine Nucleotide Signalingmentioning

confidence: 99%

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Sansom

Robson

Hartland

2008

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

SUMMARYIn humans, purinergic signaling plays an important role in the modulation of immune responses through specific receptors that recognize nucleoside tri- and diphosphates as signaling molecules. Ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTPDases) have important roles in the regulation of purinergic signaling by controlling levels of extracellular nucleotides. This process is key to pathophysiological protective responses such as hemostasis and inflammation. Ecto-NTPDases are found in all higher eukaryotes, and recently it has become apparent that a number of important parasitic pathogens of humans express surface-located NTPDases that have been linked to virulence. For those parasites that are purine auxotrophs, these enzymes may play an important role in purine scavenging, although they may also influence the host response to infection. Although ecto-NTPDases are rare in bacteria, expression of a secreted NTPDase in Legionella pneumophila was recently described. This ecto-enzyme enhances intracellular growth of the bacterium and potentially affects virulence. This discovery represents an important advance in the understanding of the contribution of other microbial NTPDases to host-pathogen interactions. Here we review other progress made to date in the characterization of ecto-NTPDases from microbial pathogens, how they differ from mammalian enzymes, and their association with organism viability and virulence. In addition, we postulate how ecto-NTPDases may contribute to the host-pathogen interaction by reviewing the effect of selected microbial pathogens on purinergic signaling. Finally, we raise the possibility of targeting ecto-NTPDases in the development of novel anti-infective agents based on potential structural and clear enzymatic differences from the mammalian ecto-NTPDases.

show abstract

Contribution of Extracellular Signal-Regulated Kinase to UTP-Induced Interleukin-6 Biosynthesis in HaCaT Keratinocytes

Cited by 16 publications

References 42 publications

Methylmercury-induced IL-6 release requires phospholipase C activities

Methylmercury-induced IL-6 release requires phospholipase C activities

Ecto-Nucleoside Triphosphate Diphosphohydrolase 2 Modulates Local ATP-Induced Calcium Signaling in Human HaCaT Keratinocytes

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Contact Info

Product

Resources

About