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

Xiangde 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

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46 Scopus citations

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

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Keywords

  • CCL2
  • IL-6
  • STAT3
  • Survival

ASJC Scopus subject areas

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

Cite this

Liu, X., Das, A. M., Seideman, J., Griswold, D., Afuh, C. N., Kobayashi, T., Abe, S., Fang, Q., Hashimoto, M., Kim, H., Wang, X., Shen, L., Kawasaki, S., & Rennard, S. I. (2007). The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6. American journal of respiratory cell and molecular biology, 37(1), 121-128. https://doi.org/10.1165/rcmb.2005-0253OC