The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6

Xiang-de Liu, Anuk M. Das, Jonathan Seideman, Don Griswold, Chantal N. Afuh, Tetsu Kobayashi, Shinji Abe, Qiuhong Fang, Mitsu Hashimoto, Huijung Kim, Xingqi Wang, Lei Shen, Shin Kawasaki, Stephen I. Rennard

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Apoptosis of lung structural cells is crucial in the process of normal tissue repair. Insufficient apoptosis of lung fibroblasts may contribute to the development of fibrosis. Since the CC chemokine ligand 2 (CCL2) is associated with fibrotic disease and the cytokine IL-6 blocks apoptosis in many cell types, we hypothesized that CCL2 may contribute to the development of lung fibrosis by inducing IL-6, which, in turn, inhibits fibroblast apoptosis. Fibroblasts were cultured in the presence of CCL2, which stimulated IL-6 production and mRNA expression in a concentration-dependent manner (250-1,000 ng/ml). This effect was mediated through the ERK1/2 signaling pathway. In addition, through a feedback loop, the secreted IL-6 activated the fibroblasts as evidenced by immunoblotting for phosphorylated STAT3. CCL2 reduced fibroblast apoptosis induced by staurosporin as detected by DNA content profiling (53.6 ± 10.8%, P < 0.05) and apoptosis induced by serum starvation as detected by COMET assay (Tail moment: 36.6 ± 9.9 of control versus 3.6 ± 1.4 of CCL2, P < 0.01). In the presence of anti-IL-6 neutralizing antibody, however, this anti-apoptotic effect of CCL2 was eliminated. These data suggest that CCL2 mediates fibroblast survival by inhibiting apoptosis through IL-6/STAT3 signaling and provides a novel mechanism through which CCL2 may contribute to the development and maintenance of lung fibrosis.

Original languageEnglish (US)
Pages (from-to)121-128
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume37
Issue number1
DOIs
StatePublished - Jul 1 2007

Fingerprint

CC Chemokines
Fibroblasts
Interleukin-6
Ligands
Apoptosis
Lung
Fibrosis
DNA Fingerprinting
MAP Kinase Signaling System
Starvation
Neutralizing Antibodies
Immunoblotting
Assays
Repair
Maintenance
Tissue
Cytokines
Feedback
Messenger RNA
DNA

Keywords

  • CCL2
  • IL-6
  • STAT3
  • Survival

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6. / Liu, Xiang-de; Das, Anuk M.; Seideman, Jonathan; Griswold, Don; Afuh, Chantal N.; Kobayashi, Tetsu; Abe, Shinji; Fang, Qiuhong; Hashimoto, Mitsu; Kim, Huijung; Wang, Xingqi; Shen, Lei; Kawasaki, Shin; Rennard, Stephen I.

In: American journal of respiratory cell and molecular biology, Vol. 37, No. 1, 01.07.2007, p. 121-128.

Research output: Contribution to journalArticle

Liu, X, Das, AM, Seideman, J, Griswold, D, Afuh, CN, Kobayashi, T, Abe, S, Fang, Q, Hashimoto, M, Kim, H, Wang, X, Shen, L, Kawasaki, S & Rennard, SI 2007, 'The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6', American journal of respiratory cell and molecular biology, vol. 37, no. 1, pp. 121-128. https://doi.org/10.1165/rcmb.2005-0253OC
Liu, Xiang-de ; Das, Anuk M. ; Seideman, Jonathan ; Griswold, Don ; Afuh, Chantal N. ; Kobayashi, Tetsu ; Abe, Shinji ; Fang, Qiuhong ; Hashimoto, Mitsu ; Kim, Huijung ; Wang, Xingqi ; Shen, Lei ; Kawasaki, Shin ; Rennard, Stephen I. / The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6. In: American journal of respiratory cell and molecular biology. 2007 ; Vol. 37, No. 1. pp. 121-128.
@article{7229738cc2ce43dab2aa5c51fa9daf4a,
title = "The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6",
abstract = "Apoptosis of lung structural cells is crucial in the process of normal tissue repair. Insufficient apoptosis of lung fibroblasts may contribute to the development of fibrosis. Since the CC chemokine ligand 2 (CCL2) is associated with fibrotic disease and the cytokine IL-6 blocks apoptosis in many cell types, we hypothesized that CCL2 may contribute to the development of lung fibrosis by inducing IL-6, which, in turn, inhibits fibroblast apoptosis. Fibroblasts were cultured in the presence of CCL2, which stimulated IL-6 production and mRNA expression in a concentration-dependent manner (250-1,000 ng/ml). This effect was mediated through the ERK1/2 signaling pathway. In addition, through a feedback loop, the secreted IL-6 activated the fibroblasts as evidenced by immunoblotting for phosphorylated STAT3. CCL2 reduced fibroblast apoptosis induced by staurosporin as detected by DNA content profiling (53.6 ± 10.8{\%}, P < 0.05) and apoptosis induced by serum starvation as detected by COMET assay (Tail moment: 36.6 ± 9.9 of control versus 3.6 ± 1.4 of CCL2, P < 0.01). In the presence of anti-IL-6 neutralizing antibody, however, this anti-apoptotic effect of CCL2 was eliminated. These data suggest that CCL2 mediates fibroblast survival by inhibiting apoptosis through IL-6/STAT3 signaling and provides a novel mechanism through which CCL2 may contribute to the development and maintenance of lung fibrosis.",
keywords = "CCL2, IL-6, STAT3, Survival",
author = "Xiang-de Liu and Das, {Anuk M.} and Jonathan Seideman and Don Griswold and Afuh, {Chantal N.} and Tetsu Kobayashi and Shinji Abe and Qiuhong Fang and Mitsu Hashimoto and Huijung Kim and Xingqi Wang and Lei Shen and Shin Kawasaki and Rennard, {Stephen I.}",
year = "2007",
month = "7",
day = "1",
doi = "10.1165/rcmb.2005-0253OC",
language = "English (US)",
volume = "37",
pages = "121--128",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "1",

}

TY - JOUR

T1 - The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6

AU - Liu, Xiang-de

AU - Das, Anuk M.

AU - Seideman, Jonathan

AU - Griswold, Don

AU - Afuh, Chantal N.

AU - Kobayashi, Tetsu

AU - Abe, Shinji

AU - Fang, Qiuhong

AU - Hashimoto, Mitsu

AU - Kim, Huijung

AU - Wang, Xingqi

AU - Shen, Lei

AU - Kawasaki, Shin

AU - Rennard, Stephen I.

PY - 2007/7/1

Y1 - 2007/7/1

N2 - Apoptosis of lung structural cells is crucial in the process of normal tissue repair. Insufficient apoptosis of lung fibroblasts may contribute to the development of fibrosis. Since the CC chemokine ligand 2 (CCL2) is associated with fibrotic disease and the cytokine IL-6 blocks apoptosis in many cell types, we hypothesized that CCL2 may contribute to the development of lung fibrosis by inducing IL-6, which, in turn, inhibits fibroblast apoptosis. Fibroblasts were cultured in the presence of CCL2, which stimulated IL-6 production and mRNA expression in a concentration-dependent manner (250-1,000 ng/ml). This effect was mediated through the ERK1/2 signaling pathway. In addition, through a feedback loop, the secreted IL-6 activated the fibroblasts as evidenced by immunoblotting for phosphorylated STAT3. CCL2 reduced fibroblast apoptosis induced by staurosporin as detected by DNA content profiling (53.6 ± 10.8%, P < 0.05) and apoptosis induced by serum starvation as detected by COMET assay (Tail moment: 36.6 ± 9.9 of control versus 3.6 ± 1.4 of CCL2, P < 0.01). In the presence of anti-IL-6 neutralizing antibody, however, this anti-apoptotic effect of CCL2 was eliminated. These data suggest that CCL2 mediates fibroblast survival by inhibiting apoptosis through IL-6/STAT3 signaling and provides a novel mechanism through which CCL2 may contribute to the development and maintenance of lung fibrosis.

AB - Apoptosis of lung structural cells is crucial in the process of normal tissue repair. Insufficient apoptosis of lung fibroblasts may contribute to the development of fibrosis. Since the CC chemokine ligand 2 (CCL2) is associated with fibrotic disease and the cytokine IL-6 blocks apoptosis in many cell types, we hypothesized that CCL2 may contribute to the development of lung fibrosis by inducing IL-6, which, in turn, inhibits fibroblast apoptosis. Fibroblasts were cultured in the presence of CCL2, which stimulated IL-6 production and mRNA expression in a concentration-dependent manner (250-1,000 ng/ml). This effect was mediated through the ERK1/2 signaling pathway. In addition, through a feedback loop, the secreted IL-6 activated the fibroblasts as evidenced by immunoblotting for phosphorylated STAT3. CCL2 reduced fibroblast apoptosis induced by staurosporin as detected by DNA content profiling (53.6 ± 10.8%, P < 0.05) and apoptosis induced by serum starvation as detected by COMET assay (Tail moment: 36.6 ± 9.9 of control versus 3.6 ± 1.4 of CCL2, P < 0.01). In the presence of anti-IL-6 neutralizing antibody, however, this anti-apoptotic effect of CCL2 was eliminated. These data suggest that CCL2 mediates fibroblast survival by inhibiting apoptosis through IL-6/STAT3 signaling and provides a novel mechanism through which CCL2 may contribute to the development and maintenance of lung fibrosis.

KW - CCL2

KW - IL-6

KW - STAT3

KW - Survival

UR - http://www.scopus.com/inward/record.url?scp=34347247309&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34347247309&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2005-0253OC

DO - 10.1165/rcmb.2005-0253OC

M3 - Article

VL - 37

SP - 121

EP - 128

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 1

ER -