The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6.
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.
Liu
Xiangde
X
University of Nebraska Medical Center, Department of Pulmonary and Critical Care Medicine, 985885 Nebraska Medical Center, Omaha, NE 68198-5885, USA.
Das
Anuk M
AM
Seideman
Jonathan
J
Griswold
Don
D
Afuh
Chantal N
CN
Kobayashi
Tetsu
T
Abe
Shinji
S
Fang
Qiuhong
Q
Hashimoto
Mitsu
M
Kim
Huijung
H
Wang
Xingqi
X
Shen
Lei
L
Kawasaki
Shin
S
Rennard
Stephen I
SI
D017209:Apoptosis; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000502:physiology*; D020552:Comet Assay; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction
D018932:Chemokine CCL2; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human