TNF-α upregulates G<sub>i</sub>α and G<sub>q</sub>α protein expression and function in human airway smooth muscle cells

Hotta, Kunihisa; Emala, Charles W.; Hirshman, Carol A.

doi:10.1152/ajplung.1999.276.3.l405

Cited by 75 publications

(82 citation statements)

References 24 publications

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“…Similar observations were made with in vitro human airway smooth muscle cells incubated with IL-1b with a decreased response in muscle stiffness to isoprenaline mediated by uncoupling of breceptors from stimulatory G s -induced activation of adenylyl cyclase, perhaps through the release of PGE 2 [68,69]. TNF-a can also induce a reduction in isoprenalinestimulated adenylyl cyclase activity [70], together with increased expression of Ga 1±2 and G q a but not of G s a proteins [71]. Passive sensitization of isolated rabbit airways with serum derived from atopic asthmatic subjects with high serum immunoglobulin (Ig)E levels demonstrated increased maximal isometric contraction and sensitivity to acetylcholine.…”

Section: Effects Of Inflammatory Factors On Airway Smooth Muscle Contsupporting

confidence: 78%

“…There was also attenuation of relaxation of acetylcholine-induced contraction to isoprenaline [72,73]. G i protein expression was increased in sensitized airway smooth muscle, due to enhanced G i a 3 subunit, and increased muscarinic M 2 receptor [71], ef-fects attributed to an induced release of IL-1b [74,75]. Autocrine pro-inflammatory signalling and altered receptor/G protein-coupled second messenger accumulation and action may contribute to increase airway smooth muscle contractility in asthma and decrease responsiveness to b-adrenergic agonists.…”

Section: Effects Of Inflammatory Factors On Airway Smooth Muscle Contmentioning

confidence: 93%

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Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Chung

2000

Eur Respir J

131

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In addition to its contractile properties, airway smooth muscle may contribute to the pathogenesis of asthma by increased proliferation, and by the expression and secretion of pro‐inflammatory cytokines and mediators. Studies of airway smooth muscle cells in culture have shown that many mitogenic mediators can induce proliferation, and that these may therefore, contribute to the increase in airway smooth muscle mass observed in asthma. Other mechanisms for airway smooth muscle proliferation include the interaction with inflammatory cells such as T‐cells and eosinophils. Airway smooth muscle cells may also be a source of inflammatory mediators and cytokines, in particular chemokines, thus implicating airway smooth muscle cells as contributors to the inflammatory mechanisms of asthma. The pro‐activating signals for converting airway smooth muscle cells into a proliferative and secretory cell in asthma are unknown, but may include viruses and immunoglobulin E. Airway smooth muscle contractility may also be altered in response to inflammation. Airway smooth muscle cells may play an important interactive role with inflammatory and other structural cells, contributing to inflammation, injury and repair of the airways. Such a recognition makes it imperative to consider the airway smooth muscle as a target of therapeutic drugs for suppressing not only the contractile but also the proliferative and secretory effects of asthma.

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Section: Effects Of Inflammatory Factors On Airway Smooth Muscle Contsupporting

confidence: 78%

Section: Effects Of Inflammatory Factors On Airway Smooth Muscle Contmentioning

confidence: 93%

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Chung

2000

Eur Respir J

131

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“…Future work can now target these newly identified areas in the TNF-α negative modulation of LTP. Evidence to connect TNF-α to GPCR signaling pathways has come mainly to date from molecular studies on cell lines showing that TNF-α leads to the activation of downstream G-protein linked signaling molecules including PI3-K, PLC, PKC and PKA (Amrani et al, 1997;Chen et al, 2000;Hotta et al, 1999;Marchetti et al, 2004;Pascual et al, 2001). Interestingly TNF-α has been shown to have a direct effect on the state of activation of the GPCR by influencing the protein levels of a negative regulator of G-protein signaling RGS-7, which is found to be highly expressed in the mammalian Insets show single traces of representative fEPSP (1, control 10 min pre-tetanus and 1 h post-tetanus; 2, 10 min pre-tetanus MCPG treated slice and 1 h post-tetanus; 3, 10 min pre-tetanus MCPG + TNF-α treated slice and 1 h post-tetanus; 4, 10 min pre-tetanus TNF-α treated slice and 1 h post-tetanus.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Cumiskey¹,

Butler²,

Moynagh³

et al. 2007

Brain Research

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Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-α, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-α have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-α on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-α is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-α is now known to cause transient increases in intracellular Ca 2+ levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca 2+ homeostasis could be involved.Ryanodine was found to significantly reverse the inhibition of LTP by TNF-α. From these studies we propose that the TNF-α inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca 2+ stores in TNF-α mediated inhibition of LTP. IntroductionThe pro-inflammatory cytokine tumor-necrosis factor (TNF)-α is elevated in the brain in a number of neuropathological states including trauma, ischemia, Parkinson's disease, multiple sclerosis and HIV-associated dementia (Iida et al., 2000;Kassiotis and Kollias, 2001;Sriram et al., 2002). The signaling mechanism underlying the ability of TNF-α to cause the cognitive dysfunction associated with many of these conditions has been probed, but to date no clear mechanistic understanding has been reached. TNF-α and IL-1β at pathophysiological levels have been shown by many authors to inhibit long-term potentiation (LTP) in the CA1 and the dentate gyrus regions of the rat hippocampus (Cunningham et al., 1996;Murray and Lynch, 1998;Tancredi et al., 1992) but not by others (Stellwagen and Malenka, 2006). IL-1β has been shown to depress NMDAreceptor mediated field potentials in the dentate gyrus (Coogan B R A I N R E S E A R C H 1 1 3 6 ( 2 0 0 7 ) 1 3 -1 9 ⁎ Corresponding author.

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“…A priori A 3 R would be expected to reduce AFC by means of its inhibitory effects on cAMP production. However, the A 3 R also signals through inositol-3-phosphate and phospholipase C to raise intracellular calcium, a pathway that increases AFC in mice and could explain the increased AFC noted in IB-MECA-treated mice (27).…”

Section: Concentrations Of Adenosine Between 10mentioning

confidence: 99%

Adenosine regulation of alveolar fluid clearance

Factor

Mutlu

Chen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Adenosine is a purine nucleoside that regulates cell function through G protein-coupled receptors that activate or inhibit adenylyl cyclase. Based on the understanding that cAMP regulates alveolar epithelial active Na ؉ transport, we hypothesized that adenosine and its receptors have the potential to regulate alveolar ion transport and airspace fluid content. Herein, we report that type 1 (A1R), 2a (A2aR), 2b (A2bR), and 3 (A3R) adenosine receptors are present in rat and mouse lungs and alveolar type 1 and 2 epithelial cells (AT1 and AT2). Rat AT2 cells generated and produced cAMP in response to adenosine, and micromolar concentrations of adenosine were measured in bronchoalveolar lavage fluid from mice. Ussing chamber studies of rat AT2 cells indicated that adenosine affects ion transport through engagement of A1R, A2aR, and/or A3R through a mechanism that increases CFTR and amiloride-sensitive channel function. Intratracheal instillation of low concentrations of adenosine (<10 ؊8 M) or either A2aR-or A3R-specific agonists increased alveolar fluid clearance (AFC), whereas physiologic concentrations of adenosine (>10 ؊6 M) reduced AFC in mice and rats via an A1R-dependent pathway. Instillation of a CFTR inhibitor (CFTRinh-172) attenuated adenosine-mediated down-regulation of AFC, suggesting that adenosine causes Cl ؊ efflux by means of CFTR. These studies report a role for adenosine in regulation of alveolar ion transport and fluid clearance. These findings suggest that physiologic concentrations of adenosine allow the alveolar epithelium to counterbalance active Na ؉ absorption with Cl ؊ efflux through engagement of the A1R and raise the possibility that adenosine receptor ligands can be used to treat pulmonary edema.active sodium transport ͉ adenosine receptors ͉ cystic fibrosis transmembrane conductance regulator P ulmonary edema is due to increased fluid flux into the airspace and impairment of the active Na ϩ transport that clears it (1-4). A variety of approaches to improve alveolar epithelial cell active Na ϩ transport for purposes of accelerating alveolar fluid clearance (AFC) have been explored in experimental systems. Of particular interest are receptor-ligand interactions that increase cAMP production in alveolar epithelial cells. Adenosine is a purine nucleoside that signals through four distinct G protein-coupled receptors, type 1 (A 1 R), type 2a (A 2a R), type 2b (A 2b R), and type 3 (A 3 R). In most cell systems, the A 1 R and A 3 R receptors inhibit adenylyl cyclase and/or lead to signaling through inositol-3-phosphate and phospholipase C. Engagement of type 2 receptors activates adenylyl cyclase by means of Gs␣ and increases cAMP levels. The ability of adenosine receptors (ARs) to couple to adenylyl cyclase led us to hypothesize that ARs might participate in regulation of alveolar epithelial active Na ϩ transport. We approached this hypothesis in rats and mice by testing whether adenosine and its receptors are present in the distal airspace and whether they affect AFC in vivo and vectorial Na ϩ...

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TNF-α upregulates G_iα and G_qα protein expression and function in human airway smooth muscle cells

Cited by 75 publications

References 24 publications

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Adenosine regulation of alveolar fluid clearance

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TNF-α upregulates Giα and Gqα protein expression and function in human airway smooth muscle cells

Cited by 75 publications

References 24 publications

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Adenosine regulation of alveolar fluid clearance

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TNF-α upregulates G_iα and G_qα protein expression and function in human airway smooth muscle cells