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PMID: 17554369 Published · ppublish English Journal Article

TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: an implication for abnormal wound healing.

The Journal of investigative dermatology ·Vol. 127 ·No. 11 ·2007-11-00 ·Pages 2645-55

Goldberg MT, Han YP, Yan C, Shaw MC, Garner WL

Abstract

Abnormal wound healing encompasses a wide spectrum, from chronic wounds to hypertrophic scars. Both conditions are associated with an abnormal cytokine profile in the wound bed. In this study, we sought to understand the dynamic relationships between myofibroblast differentiation and mechanical performance of the collagen matrix under tissue growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) stimulation. We found TGF-beta increased alpha-smooth muscle actin (alpha-SMA) and TNF-alpha alone decreased the basal alpha-SMA expression. When TGF-beta1 and TNF-alpha were both added, the alpha-SMA expression was suppressed below the baseline. Real-time PCR showed that TNF-alpha suppresses TGF-beta1-induced myofibroblast (fibroproliferative) phenotypic genes, for example, alpha-SMA, collagen type 1A, and fibronectin at the mRNA level. TNF-alpha suppresses TGF-beta1-induced gene expression by affecting its mRNA stability. Our results further showed that TNF-alpha inhibits TGF-beta1-induced Smad-3 phosphorylation via Jun N-terminal kinase signaling. Mechanical testing showed that TNF-alpha decreases the stiffness and contraction of the lattices after 5 days in culture. We proposed that changes in alpha-SMA, collagen, and fibronectin expression result in decreased contraction and stiffness of collagen matrices. Therefore, the balance of cytokines in a wound defines the mechanical properties of the extracellular matrix and optimal wound healing.

MeSH Terms
Actins/genetics,metabolism Cells, Cultured Chronic Disease Cicatrix, Hypertrophic/metabolism,pathology Collagen Type I/genetics,metabolism Dermis/cytology,metabolism Fibroblasts/cytology,metabolism Fibronectins/genetics,metabolism Humans Mitogen-Activated Protein Kinase Kinases/metabolism RNA, Messenger/genetics,metabolism Signal Transduction/physiology Smad3 Protein/metabolism Transforming Growth Factor beta1/pharmacology,physiology Tumor Necrosis Factor-alpha/physiology Wound Healing/physiology Wounds and Injuries/metabolism,pathology
Chemicals
Actins Collagen Type I Fibronectins RNA, Messenger SMAD3 protein, human Smad3 Protein Transforming Growth Factor beta1 Tumor Necrosis Factor-alpha Mitogen-Activated Protein Kinase Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Goldberg Mytien T
Division of Plastic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Han Yuan-Ping
Yan Chunli
Shaw Michael C
Garner Warren L
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Article Info
Journal
The Journal of investigative dermatology
Abbr.
J Invest Dermatol
ISSN
1523-1747
DOI
10.1038/sj.jid.5700890
Published
2007-11-00
Epub
2007-00-31
Pages
2645-55
Language
English
Region
United States
NLM ID
0426720
PMCID
PMC2366884
Subset
IM
Grants
NIAMS NIH HHS · R01 AR051558-01 · United States
NIGMS NIH HHS · R01 GM050967-06A1 · United States
External Links
PubMed source DOI: 10.1038/sj.jid.5700890 PMC Full Text View journal details
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