Abstract

Connective tissue growth factor (CTGF), a CCN family member, is a secreted protein regulating cellular functions, including fibrosis, apoptosis, adhesion, migration, differentiation, proliferation, angiogenesis, and chondrogenesis. CTGF increases proinflammatory factor production; however, inflammatory cytokine regulation by CTGF is poorly understood. The aim of this study was to identify novel biological functions and elucidate the functional mechanisms of CTGF. Specifically, the study focused on the ability of CTGF-primed monocytes to secrete interleukin 8 (CXCL8/IL-8) and determined the signaling pathways involved in CTGF-induced CXCL8/IL-8 gene regulation during inflammation. We transfected wild-type or mutant CXCL8/IL-8 promoter-derived luciferase reporter constructs into 293T cells to examine the effect of CTGF on the CXCL8/IL-8 promoter. The results showed that the activator protein-1 and nuclear factor κB binding sites of the CXCL8/IL-8 promoter are essential for CTGF-induced CXCL8/IL-8 transcription. Moreover, the CTGF-induced activation of p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase, and extracellular signal-regulated kinase (ERK) is involved in this process. In addition, adenosine–uridine-rich elements (AREs) of the CXCL8/IL-8 3′-untranslated region (3′-UTR) reduce CXCL8/IL-8 mRNA stability. To investigate whether CTGF regulates CXCL8/IL-8 gene expression at the posttranscriptional level, we transfected 293 cells with serial luciferase constructs containing different segments of the CXCL8/IL-8 3′-UTR and then stimulated the cells with CTGF. The results suggested that CTGF stabilized luciferase mRNA and increased luciferase activity by regulating the CXCL8/IL-8 3′-UTR. Moreover, the p38 MAPK pathway may contribute to CTGF-induced CXCL8/IL-8 mRNA stabilization.

Original languageEnglish
Pages (from-to)369-384
JournalImmunologic Research
Volume64
Issue number2
DOIs
Publication statusPublished - Apr 1 2016

Fingerprint

Connective Tissue Growth Factor
Interleukin-8
Gene Expression
Luciferases
Interleukin-3
3' Untranslated Regions
p38 Mitogen-Activated Protein Kinases
Chondrogenesis
Messenger RNA
Aptitude
JNK Mitogen-Activated Protein Kinases
HEK293 Cells
Extracellular Signal-Regulated MAP Kinases
Transcription Factor AP-1
RNA Stability

Keywords

  • 3′-UTR
  • AP-1
  • CTGF
  • CXCL8/IL-8
  • ERK
  • Fibrosis
  • Inflammation
  • JNK
  • NF-κB
  • p38 MAPK

ASJC Scopus subject areas

  • Immunology

Cite this

@article{69360037f02c48c39bfa05bbf7e13866,
title = "Transcriptional and posttranscriptional regulation of CXCL8/IL-8 gene expression induced by connective tissue growth factor",
abstract = "Connective tissue growth factor (CTGF), a CCN family member, is a secreted protein regulating cellular functions, including fibrosis, apoptosis, adhesion, migration, differentiation, proliferation, angiogenesis, and chondrogenesis. CTGF increases proinflammatory factor production; however, inflammatory cytokine regulation by CTGF is poorly understood. The aim of this study was to identify novel biological functions and elucidate the functional mechanisms of CTGF. Specifically, the study focused on the ability of CTGF-primed monocytes to secrete interleukin 8 (CXCL8/IL-8) and determined the signaling pathways involved in CTGF-induced CXCL8/IL-8 gene regulation during inflammation. We transfected wild-type or mutant CXCL8/IL-8 promoter-derived luciferase reporter constructs into 293T cells to examine the effect of CTGF on the CXCL8/IL-8 promoter. The results showed that the activator protein-1 and nuclear factor κB binding sites of the CXCL8/IL-8 promoter are essential for CTGF-induced CXCL8/IL-8 transcription. Moreover, the CTGF-induced activation of p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase, and extracellular signal-regulated kinase (ERK) is involved in this process. In addition, adenosine–uridine-rich elements (AREs) of the CXCL8/IL-8 3′-untranslated region (3′-UTR) reduce CXCL8/IL-8 mRNA stability. To investigate whether CTGF regulates CXCL8/IL-8 gene expression at the posttranscriptional level, we transfected 293 cells with serial luciferase constructs containing different segments of the CXCL8/IL-8 3′-UTR and then stimulated the cells with CTGF. The results suggested that CTGF stabilized luciferase mRNA and increased luciferase activity by regulating the CXCL8/IL-8 3′-UTR. Moreover, the p38 MAPK pathway may contribute to CTGF-induced CXCL8/IL-8 mRNA stabilization.",
keywords = "3′-UTR, AP-1, CTGF, CXCL8/IL-8, ERK, Fibrosis, Inflammation, JNK, NF-κB, p38 MAPK",
author = "Chien-Huang Lin and Yuan-Hung Wang and Chen, {Yu Wen} and Lin, {Yu Liang} and Bing-Chang Chen and Mei-Chieh Chen",
year = "2016",
month = "4",
day = "1",
doi = "10.1007/s12026-015-8670-0",
language = "English",
volume = "64",
pages = "369--384",
journal = "Immunologic Research",
issn = "0257-277X",
publisher = "Humana Press",
number = "2",

}

TY - JOUR

T1 - Transcriptional and posttranscriptional regulation of CXCL8/IL-8 gene expression induced by connective tissue growth factor

AU - Lin, Chien-Huang

AU - Wang, Yuan-Hung

AU - Chen, Yu Wen

AU - Lin, Yu Liang

AU - Chen, Bing-Chang

AU - Chen, Mei-Chieh

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Connective tissue growth factor (CTGF), a CCN family member, is a secreted protein regulating cellular functions, including fibrosis, apoptosis, adhesion, migration, differentiation, proliferation, angiogenesis, and chondrogenesis. CTGF increases proinflammatory factor production; however, inflammatory cytokine regulation by CTGF is poorly understood. The aim of this study was to identify novel biological functions and elucidate the functional mechanisms of CTGF. Specifically, the study focused on the ability of CTGF-primed monocytes to secrete interleukin 8 (CXCL8/IL-8) and determined the signaling pathways involved in CTGF-induced CXCL8/IL-8 gene regulation during inflammation. We transfected wild-type or mutant CXCL8/IL-8 promoter-derived luciferase reporter constructs into 293T cells to examine the effect of CTGF on the CXCL8/IL-8 promoter. The results showed that the activator protein-1 and nuclear factor κB binding sites of the CXCL8/IL-8 promoter are essential for CTGF-induced CXCL8/IL-8 transcription. Moreover, the CTGF-induced activation of p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase, and extracellular signal-regulated kinase (ERK) is involved in this process. In addition, adenosine–uridine-rich elements (AREs) of the CXCL8/IL-8 3′-untranslated region (3′-UTR) reduce CXCL8/IL-8 mRNA stability. To investigate whether CTGF regulates CXCL8/IL-8 gene expression at the posttranscriptional level, we transfected 293 cells with serial luciferase constructs containing different segments of the CXCL8/IL-8 3′-UTR and then stimulated the cells with CTGF. The results suggested that CTGF stabilized luciferase mRNA and increased luciferase activity by regulating the CXCL8/IL-8 3′-UTR. Moreover, the p38 MAPK pathway may contribute to CTGF-induced CXCL8/IL-8 mRNA stabilization.

AB - Connective tissue growth factor (CTGF), a CCN family member, is a secreted protein regulating cellular functions, including fibrosis, apoptosis, adhesion, migration, differentiation, proliferation, angiogenesis, and chondrogenesis. CTGF increases proinflammatory factor production; however, inflammatory cytokine regulation by CTGF is poorly understood. The aim of this study was to identify novel biological functions and elucidate the functional mechanisms of CTGF. Specifically, the study focused on the ability of CTGF-primed monocytes to secrete interleukin 8 (CXCL8/IL-8) and determined the signaling pathways involved in CTGF-induced CXCL8/IL-8 gene regulation during inflammation. We transfected wild-type or mutant CXCL8/IL-8 promoter-derived luciferase reporter constructs into 293T cells to examine the effect of CTGF on the CXCL8/IL-8 promoter. The results showed that the activator protein-1 and nuclear factor κB binding sites of the CXCL8/IL-8 promoter are essential for CTGF-induced CXCL8/IL-8 transcription. Moreover, the CTGF-induced activation of p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase, and extracellular signal-regulated kinase (ERK) is involved in this process. In addition, adenosine–uridine-rich elements (AREs) of the CXCL8/IL-8 3′-untranslated region (3′-UTR) reduce CXCL8/IL-8 mRNA stability. To investigate whether CTGF regulates CXCL8/IL-8 gene expression at the posttranscriptional level, we transfected 293 cells with serial luciferase constructs containing different segments of the CXCL8/IL-8 3′-UTR and then stimulated the cells with CTGF. The results suggested that CTGF stabilized luciferase mRNA and increased luciferase activity by regulating the CXCL8/IL-8 3′-UTR. Moreover, the p38 MAPK pathway may contribute to CTGF-induced CXCL8/IL-8 mRNA stabilization.

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KW - ERK

KW - Fibrosis

KW - Inflammation

KW - JNK

KW - NF-κB

KW - p38 MAPK

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