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.

CONCLUSION: 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.