scholarly journals β2-adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-arrestin2 Signaling Pathways in Human Bronchial Epithelia

2021 ◽  
Author(s):  
Rui Gang Zhang ◽  
Ya Niu ◽  
Ke Wu Pan ◽  
Hao Pang ◽  
Chung Ling Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Specific Inhibitor ◽  
Intracellular Camp ◽  
Cytokine Release ◽  
High Concentration ◽  
Airway Epithelia ◽  
Bronchial Epithelia ◽  
Adrenoceptor Agonists ◽  
Camp Receptor

Abstract Background: β 2 -adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. However, a recent study describing a side effect of aggravating eosinophilic inflammation in the mouse airway epithelia by β 2 -adrenoceptor agonists could impact the future clinical use of these bronchodilators. We previously reported that isoprenaline, via the apical and basolateral β 2 -adrenoceptor, induced Cl - secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the β 2 -adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood.Methods: We investigated β 2 -adrenoceptor-mediated signaling pathways involved in the production of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, in 16HBE14o- human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. The involvement of b-arrestin2 was examined using siRNA knockdown. Results: Both isoprenaline and formoterol (both β 2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118551 (β 2 antagonist). The PKA-specific inhibitor, H89, partially inhibited IL-6 release. Another intracellular cAMP receptor, EPAC, was not involved in IL-6 release. Isoprenaline-mediated IL-6 secretion was attenuated by dasatinib, a Src inhibitor, and PD98059, an ERK1/2 inhibitor. Isoprenaline treatment also led to ERK1/2 phosphorylation. In addition, knockdown of β-arrestin2 by siRNA specifically suppressed cytokine release when a high concentration of isoprenaline (1 mM) was used. Conclusion: Our results suggest that activation of the β 2 -adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or β-arrestin2 signaling pathways, leading to IL-6 release. Therefore, our data reveal that β 2 -adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.

scholarly journals β2-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia

Lung ◽  
2021 ◽  
Author(s):  
Rui-Gang Zhang ◽  
Ya Niu ◽  
Ke-Wu Pan ◽  
Hao Pang ◽  
Chun-Ling Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Specific Inhibitor ◽  
Intracellular Camp ◽  
Cytokine Release ◽  
High Concentration ◽  
Extracellular Signal ◽  
Bronchial Epithelia ◽  
Camp Receptor ◽  
Sirna Knockdown

Abstract Objective β2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral β2-adrenoceptor, induced Cl− secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the β2-adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood. Methods We investigated β2-adrenoceptor-mediated signaling pathways involved in the production of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, in 16HBE14o- human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. The involvement of β-arrestin2 was examined using siRNA knockdown. Results Isoprenaline and formoterol (both β2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118,551 (β2 antagonist). The PKA-specific inhibitor, H89, partially inhibited IL-6 release. Another intracellular cAMP receptor, EPAC, was not involved in IL-6 release. Isoprenaline-mediated IL-6 secretion was attenuated by dasatinib, a Src inhibitor, and PD98059, an ERK1/2 inhibitor. Isoprenaline treatment also led to ERK1/2 phosphorylation. In addition, knockdown of β-arrestin2 by siRNA specifically suppressed cytokine release when a high concentration of isoprenaline (1 mM) was used. Conclusion Our results suggest that activation of the β2-adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or β-arrestin2 signaling pathways, leading to IL-6 release. Therefore, our data reveal that β2-adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.

scholarly journals Thyrotropin-induced mitogenesis is Ras dependent but appears to bypass the Raf-dependent cytoplasmic kinase cascade.

1995 ◽  
Vol 15 (3) ◽  
pp. 1162-1168 ◽  
Author(s):  
N al-Alawi ◽  
D W Rose ◽  
C Buckmaster ◽  
N Ahn ◽  
U Rapp ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Dna Synthesis ◽  
Signaling Pathways ◽  
Cellular Growth ◽  
Intracellular Camp ◽  
Thyroid Cells ◽  
Kinase Cascade ◽  
Rat Thyroid ◽  
Stimulation Of

Cellular growth control requires the coordination and integration of multiple signaling pathways which are likely to be activated concomitantly. Mitogenic signaling initiated by thyrotropin (TSH) in thyroid cells seems to require two distinct signaling pathways, a cyclic AMP (cAMP)-dependent signaling pathway and a Ras-dependent pathway. This is a paradox, since activated cAMP-dependent protein kinase disrupts Ras-dependent signaling induced by growth factors such as epidermal growth factor and platelet-derived growth factor. This inhibition may occur by preventing Raf-1 protein kinase from binding to Ras, an event thought to be necessary for the activation of Raf-1 and the subsequent activation of the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinases (MEKs) and MAP kinase (MAPK)/ERKs. Here we report that serum-stimulated hyperphosphorylation of Raf-1 was inhibited by TSH treatment of Wistar rat thyroid cells, indicating that in this cell line, as in other cell types, increases in intracellular cAMP levels inhibit activation of downstream kinases targeted by Ras. Ras-stimulated expression of genes containing AP-1 promoter elements was similarly inhibited by TSH. On the other hand, stimulation of thyroid cells with TSH resulted in stimulation of DNA synthesis which was Ras dependent but both Raf-1 and MEK independent. We also show that Ras-stimulated DNA synthesis required the use of this kinase cascade in untreated quiescent cells but not in TSH-treated cells. These data suggest that in TSH-treated thyroid cells, Ras might be able to signal through effectors other than the well-studied cytoplasmic kinase cascade.

Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3741-3748 ◽  
Author(s):  
Ingo Ringshausen ◽  
Folker Schneller ◽  
Christian Bogner ◽  
Susanne Hipp ◽  
Justus Duyster ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Specific Inhibitor ◽  
Lymphocytic Leukemia ◽  
Antiapoptotic Proteins ◽  
Healthy Donors ◽  
Apoptosis Protein ◽  
Induced Apoptosis ◽  
Protein Kinase Cδ

In the present study we analyzed the role of phophatidylinositol-3 kinase (PI-3K) in B chronic lymphocytic leukemia (B-CLL) cells. PI-3K is activated by many stimuli and is linked to several different signaling pathways. We demonstrated that inhibition of PI-3K by a specific inhibitor, LY294002, induced apoptosis in B-CLL cells in vitro. This effect was specific for the inhibition of PI-3K because inhibition of other signaling pathways such as extracellular signaling–regulated kinase (ERK), p38, or p70S6 kinase did not affect spontaneous apoptosis. Furthermore, PI-3K was constitutively activated in freshly isolated B-CLL cells. Corresponding to enhanced apoptosis, LY294002 down-regulated expression of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and Mcl-1. Next, we investigated which factors downstream of PI-3K were activated in B-CLL cells. We demonstrated that protein kinase B/Akt is expressed in all tested CLL samples but no activation of Akt was detected. In contrast, we observed a constitutive activation of protein kinase Cδ (PKCδ) in freshly isolated B-CLL cells. PKCδ is linked to PI-3K and is phosphorylated at Thr505 in response to PI-3K activation. We further demonstrated that tyrosine phosphorylation and activity of PKCδ were dependent on PI-3K activity in B-CLL cells. Inhibition of PKCδ by the specific inhibitor Rottlerin strikingly enhanced apoptosis. In contrast, peripheral blood B cells of healthy donors were resistant to inhibition of PI-3K or PKCδ. We conclude that activated PI-3K might be important in the pathogenesis of B-CLL, and survival signals might be mediated via PKCδ. Therefore, inhibition of PI-3K or PKCδ may be an innovative approach to treat B-CLL.

scholarly journals Gastrin induces c-fosgene transcription via multiple signaling pathways

1999 ◽  
Vol 276 (2) ◽  
pp. G415-G424 ◽  
Author(s):  
Vinzenz M. Stepan ◽  
Makoto Tatewaki ◽  
Masashi Matsushima ◽  
Chris J. Dickinson ◽  
John del Valle ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Luciferase Activity ◽  
Specific Inhibitor ◽  
Regulatory Elements ◽  
Dominant Negative ◽  
Response Element ◽  
Gf 109203X ◽  
Fold Induction ◽  
Rho A

We previously observed that the trophic actions of gastrin (G17) on the AR42J rat acinar cell line are mediated by mitogen-activated protein kinase (MAPK)-induced c- fos gene transcription via protein kinase C (PKC)-dependent and -independent pathways. In this study, we further investigated the signaling pathways that target c- fos in response to G17. G17 led to a sixfold induction in luciferase activity in cells transfected with plasmids containing the −356+109 sequence of the murine c- fos promoter, which includes the Sis-inducible element (SIE), serum response element (SRE), and the Ca2+/cAMP response element (CRE) regulatory elements. Addition of either the selective PKC inhibitor GF-109203X or the MAPK/extracellular signal-regulated kinase inhibitor PD-98059 resulted in an 80% reduction in luciferase activity. G17 induced the transcriptional activity of both Elk-1 and Sap-1a, transcription factors that bind to the E26 transformation specific (Ets) DNA sequence of the SRE, and this effect was inhibited by both GF-109203X and PD-98059. Point mutations in the Ets sequence led to a 4-fold induction of c- fos transcription stimulated by G17 and to a 1.3-fold induction in response to epidermal growth factor (EGF). In contrast, mutations in the CA rich G (CArG) sequence of the SRE prevented transcriptional activation by both G17 and EGF. G17 induction of the Ets mutant construct was unaffected by either GF-109203X or PD-98059. Because activation of the SRE involves the small GTP-binding protein Rho A, we examined the role of Rho A in G17 induction of c- fos transcription. Inactivation of Rho A by either the specific inhibitor C3 or by expression of a dominant negative Rho A gene inhibited G17 induction of both the wild-type and the Ets mutant constructs by 60%. C3 also inhibited G17-stimulated AR42J cell proliferation. Thus G17 targets the c- fos promoter CArG sequence via Rho A-dependent pathways, and Rho A appears to play an important role in the regulation of the trophic action of G17.

scholarly journals Phosphodiesterase Inhibitors SuppressLactobacillus caseiCell-Wall-Induced NF-κB and MAPK Activations and Cell Proliferation through Protein Kinase A—or Exchange Protein Activated by cAMP-Dependent Signal Pathway

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Takekatsu Saito ◽  
Naotoshi Sugimoto ◽  
Kunio Ohta ◽  
Tohru Shimizu ◽  
Kaori Ohtani ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Signaling Pathways ◽  
Inflammatory Responses ◽  
Phosphodiesterase Inhibitor ◽  
Mapk Signaling ◽  
Intracellular Camp ◽  
Kinase A ◽  
Exchange Protein

Specific strains ofLactobacillushave been found to be beneficial in treating some types of diarrhea and vaginosis. However, a high mortality rate results from underlying immunosuppressive conditions in patients withLactobacillus caseibacteremia. Cyclic AMP (cAMP) is a small second messenger molecule that mediates signal transduction. The onset and progression of inflammatory responses are sensitive to changes in steady-state cAMP levels.L. caseicell wall extract (LCWE) develops arteritis in mice through Toll-like receptor-2 signaling. The purpose of this study was to investigate whether intracellular cAMP affects LCWE-induced pathological signaling. LCWE was shown to induce phosphorylation of the nuclear factorκB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways and cell proliferation in mice fibroblast cells. Theophylline and phosphodiesterase inhibitor increased intracellular cAMP and inhibited LCWE-induced cell proliferation as well as phosphorylation of NF-κB and MAPK. Protein kinase A inhibitor H89 prevented cAMP-induced MAPK inhibition, but not cAMP-induced NF-κB inhibition. An exchange protein activated by cAMP (Epac) agonist inhibited NF-κB activation but not MAPK activation. These results indicate that an increase in intracellular cAMP prevents LCWE induction of pathological signaling pathways dependent on PKA and Epac signaling.

Effect of nitric oxide on Sertoli cell microtubule of piglets

2009 ◽  
Vol 6 (3) ◽  
pp. 257-263 ◽  
Author(s):  
Yang Li ◽  
Wang Xian-zhong ◽  
Yang Meng-bo ◽  
Zhang Jia-hua
Keyword(s):  
Nitric Oxide ◽  
Enzyme Activity ◽  
Protein Kinase ◽  
Cell Viability ◽  
Sodium Nitroprusside ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
High Concentration ◽  
Treatment Results ◽  
Anti Oxidant

AbstractTo illustrate the effect of nitric oxide (NO) on the microtubules of Sertoli cells (SC), SCs of piglets were treated with sodium nitroprusside (SNP). Changes in cell viability, anti-oxidant activity, enzyme activity and p38 mutagen-activated protein kinase (p38MAPK) activation were detected. The results were as follows. A low concentration of NO can keep SC microtubule and cell viability normal, and a high concentration of NO could increase p38MAPK activation, decrease anti-oxidant activity and transferrin secretion, and destroy the structure and distribution of the microtubules. The results suggest that SNP treatment results in an increase in NO in SCs and decreased cell anti-oxidant activity. The high concentration of NO destroys cell microtubules by activating p38MAPK.

scholarly journals STO-609, a specific inhibitor of the Ca2+/calmodulin-dependent protein kinase kinase.

2003 ◽  
Vol 278 (6) ◽  
pp. 4368
Author(s):  
Hiroshi Tokumitsu ◽  
Hiroyuki Inuzuka ◽  
Yumi Ishikawa ◽  
Masahiko Ikeda ◽  
Ikutaro Saji ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Specific Inhibitor ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Protein Kinase Kinase

scholarly journals Targeted disruption of PKC from AKAP Signaling Complexes

2021 ◽  
Author(s):  
Ameya J. Limaye ◽  
George N. Bendzunas ◽  
Eileen Kennedy
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Targeted Disruption ◽  
Physiological Processes ◽  
Kinase C ◽  
P Protein

Protein Kinase C (PKC) is a member of the AGC subfamily of kinases and regulates a wide array of signaling pathways and physiological processes. Protein-protein interactions involving PKC and its...

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