IFN-gamma fails to antagonize fibrotic effect of TGF-beta on keloid-derived dermal fibroblasts.
BACKGROUND
Interferon-gamma (IFN-gamma) has been noted as a potential therapeutic agent for various fibrotic disorders, in part, through its antagonistic effect on a fibrogenic cytokine, transforming growth factor-beta (TGF-beta). Keloid is a fibrotic skin disorder that results in an excessive deposition of extracellular matrix, which is associated with altered-expression of or -responses to TGF-beta in dermal fibroblasts.


OBJECTIVE
We sought to determine whether IFN-gamma antagonized TGF-beta-mediated fibrotic response in keloid-derived dermal fibroblasts.


METHODS
Type I collagen production, fibroblast contractile activity, and alpha-smooth muscle actin (alpha-SMA) expression were assessed by using Western blotting, an in vitro type I collagen gel contraction assay, and immunofluorescence study in normal and keloid-derived human dermal fibroblasts in the presence or absence of IFN-gamma and/or TGF-beta.


RESULTS
In contrast to normal dermal fibroblasts, IFN-gamma did not inhibit TGF-beta-induced type I collagen production, contractile activity, and alpha-SMA expression in keloid-derived dermal fibroblasts. In addition, keloid-derived dermal fibroblasts constitutively expressed type I collagen and alpha-SMA with increased capacity to contract a collagen matrix.


CONCLUSIONS
IFN-gamma failed to antagonize TGF-beta-mediated fibrotic response in keloid-derived dermal fibroblasts. Thus, IFN-gamma may not be therapeutically useful for keloid and clarification of the molecular mechanisms underlying the IFN-gamma resistance should be investigated for therapeutic application of IFN-gamma for keloid.
Hasegawa
Toshio
T
Department of Dermatology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Nakao
Atsuhito
A
Sumiyoshi
Koji
K
Tsuboi
Ryoji
R
Ogawa
Hideoki
H
D000199:Actins / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects / Q000502:physiology; D024042:Collagen Type I / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis / Q000517:prevention & control; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007627:Keloid / Q000378:metabolism / Q000473:pathology*; D009130:Muscle, Smooth / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000199:Actins; D024042:Collagen Type I; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase