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.
authors: University of Nebraska Medical Center, Department of Pulmonary and Critical Care Medicine, 985885 Nebraska Medical Center, Omaha, NE 68198-5885, USA.
authors: Xiangde
authors: X
authors: Liu
authors: Anuk M
authors: AM
authors: Das
authors: Jonathan
authors: J
authors: Seideman
authors: Don
authors: D
authors: Griswold
authors: Chantal N
authors: CN
authors: Afuh
authors: Tetsu
authors: T
authors: Kobayashi
authors: Shinji
authors: S
authors: Abe
authors: Qiuhong
authors: Q
authors: Fang
authors: Mitsu
authors: M
authors: Hashimoto
authors: Huijung
authors: H
authors: Kim
authors: Xingqi
authors: X
authors: Wang
authors: Lei
authors: L
authors: Shen
authors: Shin
authors: S
authors: Kawasaki
authors: Stephen I
authors: SI
authors: Rennard
mesh_terms: 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
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human