MAPK signaling pathways regulate IL-8 mRNA stability and IL-8 protein expression in cystic fibrosis lung epithelial cell lines

Bhattacharyya, Somnath; Gutti, Usha; Mercado, Jose; Moore, Chad; Pollard, Harvey B.; Biswas, Roopa

doi:10.1152/ajplung.00051.2010

Cited by 50 publications

(55 citation statements)

References 22 publications

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“…7, the effect of raising miR-155, lowering SHIP1, and activating PI3K/ Akt is to activate MAPKs, thereby stabilizing IL-8 mRNA and increasing the levels of IL-8 protein expression. These data thus lend further support to the concept that the proinflammatory phenotype of the CF airway is due to increased stability of the IL-8 mRNA and subsequent increased expression of IL-8 protein (12,46). SHIP1 and PI3K/Akt Signaling-The only predicted and validated microRNA to target SHIP1 is miR-155 (44), and the connection of SHIP1 to activation of PI3K/AKT signaling has been validated using both pharmacologic and molecular methods.…”

Section: Discussionsupporting

confidence: 54%

“…Furthermore, we have shown here that in CF cells, intrinsic activation of PI3K signaling occurs through intrinsic miR-155-dependent down-regulation of SHIP1. This leads to activation of downstream MAPKs with consequent stabilization of IL-8 mRNA and hyperexpression of IL-8 protein (46). SHIP1, an inositol 5-phosphatase, controls PI3K/Akt signaling by hydrolyzing the PIP 3 product of PI3K enzymatic activity to PIP 2 .…”

Section: Discussionmentioning

confidence: 99%

“…miR-155-dependent Activation of PI3K/Akt Signaling and Downstream Activation of MAPKs-In CF cells, both in vitro and in vivo, we have previously shown that increased levels of MAPK signaling contribute to IL-8 mRNA stabilization (46). Nonetheless, in these previous studies, the CF-specific driver for MAPK activation had yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

“…In previous work, we have shown that IL-8 mRNA is greatly stabilized in CF cells, both in vitro and in vivo, and that IL-8 protein expression rates were also elevated as a consequence (12,46). We therefore hypothesized that if SHIP1 levels were exogenously elevated in CF cells, then the half-life of IL-8 mRNA would be reduced, and the expression levels of IL-8 protein would also be reduced.…”

Section: Mir-155 Targets Ship1 In Cf Cells To Promote Mrna Stability mentioning

confidence: 97%

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Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8

Bhattacharyya

Balakathiresan²,

Dalgard

et al. 2011

Journal of Biological Chemistry

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191

163

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Cystic Fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyperexpression of IL-8 protein. However, the mechanistic link between mutations in CFTR and acquisition of the proinflammatory phenotype in the CF airway has remained elusive. We hypothesized that specific microRNAs (miRNAs) might mediate this linkage. To identify the potential link, we screened an miRNA library for differential expression in ⌬F508-CFTR and wild type CFTR lung epithelial cell lines. Of 22 differentially and significantly expressed miRNAs, we found that expression of miR-155 was more than 5-fold elevated in CF IB3-1 lung epithelial cells in culture, compared with control IB3-1/S9 cells. Clinically, miR-155 was also highly expressed in CF lung epithelial cells and circulating CF neutrophils biopsied from CF patients. We report here that high levels of miR-155 specifically reduced levels of SHIP1, thereby promoting PI3K/Akt activation. However, overexpressing SHIP1 or inhibition of PI3K in CF cells suppressed IL-8 expression. Finally, we found that phospho-Akt levels were elevated in CF lung epithelial cells and were specifically lowered by either antagomir-155 or elevated expression of SHIP1. We therefore suggest that elevated miR-155 contributes to the proinflammatory expression of IL-8 in CF lung epithelial cells by lowering SHIP1 expression and thereby activating the PI3K/Akt signaling pathway. These data suggest that miR-155 may play an important role in the activation of IL-8-dependent inflammation in CF.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mir-155 Targets Ship1 In Cf Cells To Promote Mrna Stability mentioning

confidence: 97%

See 2 more Smart Citations

Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8

Bhattacharyya

Balakathiresan²,

Dalgard

et al. 2011

Journal of Biological Chemistry

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191

163

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“…Both erK1/2 and p38 MApK signaling pathways are associated with tumor cell migration (18). In various cell types and conditions, the regulation of IL-8 mrNA stability is a well-accepted and important mechanism of IL-8 mrNA expression (25,30). Accumulating evidence has revealed that the p38 MApK signaling pathway, and to a minor extent erK1/2, controls IL-8 mrNA stability (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine inhibits migration of SKOV3 human ovarian carcinoma cells and decreases the expression of interleukin-8 via the ERK1/2, p38 and AP-1 signaling pathways

Yang¹

2011

Oncol Rep

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Abstract. expression by melanoma cells may influence their metastatic capabilities. tetramethylpyrazine (tMp) from Ligusticum wallichil Franch. possesses anti-inflammatory and antitumor activities. It has recently been suggested that autocrine IL-8 may play a role in tumor cell survival, invasion and migration. the role of tMp in association with IL-8 in the tumor cell migratory process remains unclear. the purpose of the present study was to determine whether TMP influences the migratory ability of a human ovarian carcinoma cell line (sKOV3) via regulation of IL-8 expression in vitro. Cell counts showed that treatment of sKOV3 with tMp (25-100 µg/ml) for 24 h did not decrease cell numbers, while an effect of tMp on the down-regulation of the expression of IL-8 was observed. In addition, migration of sKOV3 cells was suppressed after treatment with tMp (25-100 µg/ml) for 24 h. therefore, expression of IL-8 by sKOV3 cells correlates with their metastatic potential. Western blot analysis revealed that erK1/2 and p38 phosphorylation was blocked by tMp. Furthermore, IL-8 mrNA expression was inhibited significantly after co-incubation with PD98059 (erK inhibitor) and sB203580 (p38 inhibitor), respectively. Notably, these changes were the results of activator protein-1 (Ap-1) activity suppression rather than that of NF-κB. Our data suggest that tMp may inhibit tumor cell invasion and migration, at least in part, through its down-regulation of IL-8 expression. Our results provide evidence that anti-inflammation plays an important role in integrative cancer therapies. IntroductionThe functional relationship between inflammation and cancer is widely accepted. Inflammation is a critical component of tumor progression, such as tumor cell metastasis (1). Metastasis, a complex and multiple process in which tumor cells spread from the primary site to distant organs, is one of the most common causes of morbidity and mortality in patients with ovarian carcinoma. the migratory capacity of cancer cells can be regulated by various factors including growth factors and cytokines (2), such as CXC-chemokine IL-8 (CXCL-8), a pro-inflammatory cytokine initially described as a neutrophil and monocyte chemoattactant, which modulates monocyte adhesion to endothelium and vascular smooth muscle cell migration (3-5). A direct correlation has also been demonstrated between overexpressed IL-8 and the increased metastasis of tumor cells (6-8). Evidence has confirmed that tumor cells are able to respond to the autocrine release of IL-8, which enables tumor cells to have an additional growth and progression advantage (9). De Larco et al (10) reported that the concentration gradient of IL-8 produced by tumor cells, which is higher at the primary tumor site than that at noncancerous sites, promotes distant metastasis of tumor cells. Moreover, IL-8 can recruit neutrophils to the primary tumor site through its chemoattractant capacity. In response to IL-8, the recruited neutrophils release proteases and heparanase which hydrolyze components of the ext...

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Regulation of mRNA turnover in cystic fibrosis lung disease

2016

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Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, F508del-CFTR being the most frequent mutation. The CF lung is characterized by a hyperinflammatory phenotype and is regulated by multiple factors that coordinate its pathophysiology. In CF the expression of CFTR as well as proinflammatory genes are regulated at the level of messenger RNA (mRNA) stability, which subsequently affect translation. These mechanisms are mediated by inflammatory RNA-binding proteins as well as small endogenous noncoding microRNAs, in coordination with cellular signaling pathways. These regulatory factors exhibit altered expression and function in vivo in the CF lung, and play a key role in the pathophysiology of CF lung disease. In this review, we have described the role of mRNA stability and associated regulatory mechanisms in CF lung disease. WIREs RNA 2017, 8:e1408. doi: 10.1002/wrna.1408 For further resources related to this article, please visit the WIREs website.

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MAPK signaling pathways regulate IL-8 mRNA stability and IL-8 protein expression in cystic fibrosis lung epithelial cell lines

Cited by 50 publications

References 22 publications

Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8

Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8

Tetramethylpyrazine inhibits migration of SKOV3 human ovarian carcinoma cells and decreases the expression of interleukin-8 via the ERK1/2, p38 and AP-1 signaling pathways

Regulation of mRNA turnover in cystic fibrosis lung disease

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