CCL18-stimulated upregulation of collagen production in lung fibroblasts requires Sp1 signaling and basal Smad3 activity

被引:53
|
作者
Luzina, IG
Tsymbalyuk, N
Choi, J
Hasday, JD
Atamas, SP
机构
[1] Univ Maryland, Sch Med, Dept Med, Baltimore VA Med Ctr, Baltimore, MD 21201 USA
[2] Baltimore VA Med Ctr, Res Serv, Baltimore, MD USA
关键词
D O I
10.1002/jcp.20452
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
ACC chemokine CCL18 stimulates collagen production in pulmonary fibroblasts through an unknown signaling mechanism. In this study, involvement of Sp1 and Smad3 in CCL18 signaling in primary human pulmonary fibroblast cultures was investigated. Phosphorylation of Sp1, DNA-binding by Sp1, and the activity of an Sp1-dependent reporter were all increased in response to CCL1 8 stimulation. CCL18 did not stimulate a detectable increase in Smad3 phosphorylation or Smad3/4 DNA-binding activity, although some basal phosphorylation and DNA binding by Smad3/4 were noted. Transient overexpression of dominant negative mutants of Sp1 and Smad3 abrogated CCL18-dependent upregulation as well as basal production of collagen. These observations suggested that CCL18 activates collagen production in pulmonary fibroblasts through an Sp1-dependent pathway that also requires basal Smac13 activity. Possible involvement of autocrine TGF-beta in CCL18 signaling was considered. CCL18 stimulated increases in collagen mRNA and protein production without detectable changes in TGF-beta 1, -beta 2, and -beta 3 mRNA or protein levels. Neutralizing anti-TGF-beta antibodies, latency-associated peptide, ALK5-specific inhibitor SD431542, and an inhibitor of the protease-dependent TGF-beta activation aprotinin, each failed to block CCL18-stimulated collagen production. These observations suggest that both CCLI 8 signaling in pulmonary fibroblasts and basal Smad3 activity are independent of autocrine TGF-beta. J. Cell. Physiol. 206: 221 -228, 2006. (c) 2005 Wiley-Liss, Inc.
引用
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页码:221 / 228
页数:8
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