scholarly journals Down-regulation of Cytokine-induced Interleukin-8 Requires Inhibition of p38 Mitogen-activated Protein Kinase (MAPK) via MAPK Phosphatase 1-dependent and -independent Mechanisms

2011 ◽  
Vol 286 (18) ◽  
pp. 15998-16007 ◽  
Author(s):  
Nurlan Dauletbaev ◽  
Daniel Eklove ◽  
Nadir Mawji ◽  
Michele Iskandar ◽  
Sergio Di Marco ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
P38 Mapk ◽  
Mrna Stability ◽  
Airway Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Airway Epithelial ◽  
Down Regulation ◽  
Mitogen Activated Protein ◽  
Mapk Phosphatase

Down-regulation of overabundant interleukin (IL)-8 present in cystic fibrosis (CF) airways could ease excessive neutrophil burden and its deleterious consequences for the lung. IL-8 production in airway epithelial cells, stimulated with e.g. inflammatory cytokines IL-1β and tumor necrosis factor (TNF)-α, is regulated by several signaling pathways including nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK). We previously demonstrated that the anti-inflammatory drugs dexamethasone and ibuprofen suppress NF-κB; however, only dexamethasone down-regulates cytokine-induced IL-8, highlighting the importance of non-NF-κB mechanisms. Here, we tested the hypothesis that down-regulation of cytokine-induced IL-8 requires modulation of the MAPK phosphatase (MKP)-1/p38 MAPK/mRNA stability pathway. The effects of dexamethasone (5 nm) and ibuprofen (480 μm) on this pathway and IL-8 were studied in CF (CFTE29o−, CFBE41o−) and non-CF (1HAEo−) airway epithelial cells. We observed that dexamethasone, but not ibuprofen, destabilizes IL-8 mRNA and up-regulates MKP-1 mRNA. Further, siRNA silencing of MKP-1, via p38 MAPK, leads to IL-8 overproduction and diminishes the anti-IL-8 potential of dexamethasone. However, MKP-1 overexpression does not significantly alter IL-8 production. By contrast, direct inhibition of p38 MAPK (inhibitor SB203580) efficiently suppresses IL-8 with potency comparable with dexamethasone. Similar to dexamethasone, SB203580 decreases IL-8 mRNA stability. Dexamethasone does not affect p38 MAPK activation, which excludes its effects upstream of p38 MAPK. In conclusion, normal levels of MKP-1 are necessary for a full anti-IL-8 potential of pharmacological agents; however, efficient pharmacological down-regulation of cytokine-induced IL-8 also requires direct effects on p38 MAPK and mRNA stability independently of MKP-1.

High Concentration of Insulin Induces MUC5AC Expression via Phosphoinositide 3 Kinase/AKT and Mitogen-activated Protein Kinase Signaling Pathways in Human Airway Epithelial Cells

2018 ◽  
Vol 32 (5) ◽  
pp. 350-358 ◽  
Author(s):  
Hyung Gyun Na ◽  
Yong-Dae Kim ◽  
Chang Hoon Bae ◽  
Yoon Seok Choi ◽  
Hyun Jung Jin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
Airway Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Airway Epithelial ◽  
High Concentration ◽  
Human Airway ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Background Insulin is involved in a glucose homeostatic regulation and a cellular metabolism via phosphorylation of phosphoinositide 3 kinase (PI3K) pathway and mitogen-activated protein kinase (MAPK) pathway. Hyperinsulinemia reduces insulin sensitivity and is an obvious potential factor affecting airway inflammation in chronic airway diseases. MUC5AC is a major secreted mucin, which plays a critical role in inflammatory response in the respiratory tract. However, the relationship between insulin and MUC5AC expression has not been studied. Objective This study investigated the effect and the brief signaling pathway of high concentration of insulin (HI) on MUC5AC expression in human airway epithelial cell. Methods In NCI-H292 cells and primary cultures of normal nasal epithelial cells, the effect and signaling pathway of HI on MUC5AC expression were investigated using reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, enzyme immunoassay, and immunoblot analysis with several specific inhibitors and small interfering RNA (siRNA). Results HI significantly increased MUC5AC expression and activated PI3K/AKT, extracellular signal-related kinase 1/2 (ERK1/2) and p38 MAPKs. The specific PI3K and AKT inhibitor as well as knockdown of AKT1 and AKT2 by the respective siRNAs significantly blocked HI-mediated expression of MUC5AC. Meanwhile, the specific ERK1/2 MAPK and p38 MAPK inhibitor as well as knockdown of ERK1, ERK2, and p38 MAPK by the respective siRNAs also attenuated HI-induced expression of MUC5AC. Conclusion The results of this study suggest that HI induces MUC5AC expression via PI3K/AKT and MAPK signaling pathways in human airway epithelial cells.

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