The Regulatory Role of Rolipram on Inflammatory Mediators and Cholinergic/Adrenergic Stimulation-Induced Signals in Isolated Primary Mouse Submandibular Gland Cells

Lee, Dong Un; Shin, Dong Min; Hong, Jeong Hee

doi:10.1155/2016/3745961

Cited by 15 publications

(21 citation statements)

References 37 publications

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“…A large panel of PDEs has been shown to regulate cAMP levels thus modulating the PKA activity and NLRP3 activation. For example, the PED4 inhibitor Rolipram has been shown to inhibit NLRP3 inflammasome activation in submandibular gland cells ( 59 ). Although we had shown that AC inhibitor could reverse baicalin-mediated suppression of NLRP3, our data does not exclude the possibility that baicalin may regulate PKA signaling by affecting the activity of PDEs.…”

Section: Discussionmentioning

confidence: 99%

Baicalin Inhibits NOD-Like Receptor Family, Pyrin Containing Domain 3 Inflammasome Activation in Murine Macrophages by Augmenting Protein Kinase A Signaling

Liang

Mai

et al. 2017

Front. Immunol.

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The flavonoid baicalin has been reported to possess potent anti-inflammatory activities by suppressing inflammatory signaling pathways. However, whether baicalin can suppress the activation of NOD-like receptor (NLR) family, pyrin containing domain 3 (NLRP3) inflammasome in macrophages is largely unknown. Here, we showed that baicalin treatment dose-dependently inhibited adenosine triphosphate (ATP) or nigericin-induced NLRP3 inflammasome activation, as revealed by the decreased release of mature interleukin (IL)-1β, active caspase-1p10, and high-mobility group box-1 protein from lipopolysaccharide (LPS)-primed bone marrow-derived macrophages. The formation of ASC specks, a critical marker of NLRP3 inflammasome assembly, was robustly inhibited by baicalin in the macrophages upon ATP or nigericin stimulation. All these inhibitory effects of baicalin could be partly reversed by MDL12330A or H89, both of which are inhibitors of the protein kinase A (PKA) signaling pathway. Consistent with this, baicalin strongly enhanced PKA-mediated phosphorylation of NLRP3, which has been suggested to prevent ASC recruitment into the inflammasome. Of note, the PKA inhibitor H89 could block baicalin-induced NLRP3 phosphorylation on PKA-specific sites, further supporting PKA’s role in this process. In addition, we showed that when administered pre and post exposure to Escherichia coli infection baicalin treatment significantly improved mouse survival in bacterial sepsis. Baicalin administration also significantly reduced IL-1β levels in the sera of bacterial infected mice. Altogether, our results revealed that baicalin inhibited NLRP3 inflammasome activation at least partly through augmenting PKA signaling, highlighting its therapeutic potential for the treatment of NLRP3-related inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Baicalin Inhibits NOD-Like Receptor Family, Pyrin Containing Domain 3 Inflammasome Activation in Murine Macrophages by Augmenting Protein Kinase A Signaling

Liang

Mai

et al. 2017

Front. Immunol.

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“…Irradiation induces loss of STIM1, which is essential for Ca 2+ influx from extracellular buffer and sustained elevation of intracellular Ca 2+ (17). A phosphodiesterase inhibitor, rolipram, which suppresses ROS production, enhanced CCh-induced Ca 2+ signaling in submandibular gland cells (18). During isolation from the glands, the cells were exposed to ROS, which may depress Ca 2+ signaling.…”

Section: Discussionmentioning

confidence: 99%

Suppression of parotid acinar cell dysfunction by the free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one

et al. 2019

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Salivary gland atrophy and consequent hyposalivation are serious problems in clinical dentistry, as saliva regulates the environment of the oral cavity. To clarify the mechanisms underlying salivary gland dysfunction, a system for primary culture of parotid acinar cells has been established. It has been reported previously that the process of cell isolation from parotid glands triggers stress signaling mediated by Src and p38 mitogen-activated protein (MAP) kinase (p38), leading to dedifferentiation of acinar cells, and that an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor suppresses this activation of Src and p38, suggesting that reactive oxygen species initiate the dedifferentiation signal. The present study examined the effect of a free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (also termed MCI-186 or edaravone), on activation of the stress signal and the secretory function of parotid acinar cells. Activation of p38 during cell isolation was suppressed by addition of MCI-186. The retention of the activity of amylase, a major salivary protein, and the number of amylase-containing secretory granules were improved by isolation and culture in the presence of MCI-186. In addition, calcium elevation upon stimulation with a muscarinic agonist was higher in MCI-186-treated cells than in untreated cells. These results suggest that MCI-186 (edaravone) is a promising agent for prevention of salivary gland dysfunction.

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“…Isolated SMG acini and ducts were plated on glass coverslips for 5 min at room temperature prior to fixation with chilled methanol or 4% paraformaldehyde for 10 min. After fixation, immunostaining was performed as described previously (Lee et al, 2016 ) using 1:100 dilutions of the α2 A -adrenergic receptor, PDE4, and ZO-1 antibodies. Briefly, the cells were incubated with the primary antibodies overnight at 4°C, then washed with 5% BSA/PBS.…”

Section: Methodsmentioning

confidence: 99%

“…SMG cells were isolated and stimulated with the indicated components for 1 h. Cell lysates were prepared in lysis buffer (containing [mM] 20 Tris, 150 NaCl, 2 EDTA, 1% Triton X-100, and a protease inhibitor mixture) and treated as previously described (Lee et al, 2016 ). Briefly, proteins were denatured via incubation in SDS sample buffer at 37°C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…In the salivary glands, PDE4 is involved in the release of amylase from parotid acinar cells (Satoh et al, 2009 ). The PDE4 inhibitor rolipram regulates ductal

secretion and confers a protective effect on lipopolysaccharide (LPS)-induced Ca 2+ signaling and inflammatory cytokine expression (Lee et al, 2016 ). Although, it has been suggested that Dex is involved in cAMP-mediated cellular events (Rouch et al, 1997 ), it is unknown whether Dex-modulation of cAMP levels plays a role in ion transporter activity during salivary secretion or whether Dex modulates expression of cAMP-dependent PDE4 of the salivary glands.…”

Section: Introductionmentioning

confidence: 99%

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Two Phase Modulation of NH4+ Entry and Cl−/HCO3- Exchanger in Submandibular Glands Cells by Dexmedetomidine

Lee

Park

et al. 2017

Front. Physiol.

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Dexmedetomidine (Dex), a highly selective α2-adrenoceptor agonist, attenuates inflammatory responses induced by lipopolysaccharide (LPS) and induces sedative and analgesic effects. Administration of Dex also reduces salivary secretion in human subjects and inhibits osmotic water permeability in rat cortical collecting ducts. However, little is known about the mechanisms underlying the effects of Dex on salivary glands fluid secretion. We demonstrated the α2-adrenoceptor expression in the basolateral membrane of mouse submandibular glands (SMG). To investigate fluid secretion upon treatment with Dex, we studied the effects of Dex on the activity of Na+-K+-2Cl− cotransporter1 (NKCC1) and Cl−/HCO3- exchange (CBE), and on downstream pro-inflammatory cytokine expression in isolated primary mouse SMG cells. Dex acutely increased CBE activity and NKCC1-mediated and independent NH4+ entry in SMG duct cells, and enhanced ductal fluid secretion in a sealed duct system. Dex showed differential effects on cholinergic/adrenergic stimulations and inflammatory mediators, histamine, and LPS, stimulations-induced Ca2+ in mouse SMG cells. Both, histamine- and LPS-induced intracellular Ca2+ increases were inhibited by Dex, whereas carbachol-stimulated Ca2+ signals were not. Long-lasting (2 h) treatment with Dex reduced CBE activity in SMG and in human submandibular glands (HSG) cells. Moreover, when isolated SMG cells were stimulated with Dex for 2 h, phosphodiesterase 4D (PDE4D) expression was enhanced. These results confirm the anti-inflammatory properties of Dex on LPS-mediated signaling. Further, Dex also inhibited mRNA expression of interleukin-6 and NADPH oxidase 4. The present study also showed that α2-adrenoceptor activation by Dex reduces salivary glands fluid secretion by increasing PDE4D expression, and subsequently reducing the concentration of cAMP. These findings reveal an interaction between the α2-adrenoceptor and PDE4D, which should be considered when using α2-adrenoceptor agonists as sedative or analgesics.

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The Regulatory Role of Rolipram on Inflammatory Mediators and Cholinergic/Adrenergic Stimulation-Induced Signals in Isolated Primary Mouse Submandibular Gland Cells

Cited by 15 publications

References 37 publications

Baicalin Inhibits NOD-Like Receptor Family, Pyrin Containing Domain 3 Inflammasome Activation in Murine Macrophages by Augmenting Protein Kinase A Signaling

Baicalin Inhibits NOD-Like Receptor Family, Pyrin Containing Domain 3 Inflammasome Activation in Murine Macrophages by Augmenting Protein Kinase A Signaling

Suppression of parotid acinar cell dysfunction by the free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one

Two Phase Modulation of NH4+ Entry and Cl−/HCO3- Exchanger in Submandibular Glands Cells by Dexmedetomidine

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