Smad7 Ameliorates TGF-beta-Mediated Skin Inflammation and Associated Wound Healing Defects but Not Susceptibility to Experimental Skin Carcinogenesis

摘要

We assessed the roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGF beta 1/K5.Smad7 bigenic (double transgenic) mice, Smad7 transgene expression reversed transforming growth factor (TGF)-beta 1 transgene-induced inflammation, fibrosis, and subsequent epidermal hyperplasia and molecularly abolished TGF-beta and NF-kappa B activation. Next, we produced recombinant human Smad7 protein with a Tat-tag (Tat-Smad7) that rapidly enters cells. Subcutaneous injection of Tat-Smad7 attenuated infiltration of F4/80(+) and CD11b(+) leukocytes and alpha-smooth muscle actin(+) fibroblasts before attenuating epidermal hyperplasia in K5.TGF beta 1 skin. Furthermore, topically applied Tat-Smad7 on K5.TGF beta 1 skin wounds accelerated wound closure, with improved re-epithelialization and reductions in inflammation and fibrotic response. A short treatment with Tat-Smad7 was also sufficient to reduce TGF-beta and NF-kappa B signaling in K5.TGF beta 1 skin and wounds. Relevant to the clinic, we found that human diabetic wounds had elevated TGF-beta and NF-kappa B signaling compared with normal skin. To assess the oncogenic risk of a potential Smad7-based therapy, we exposed K5. Smad7 skin to chemical carcinogenesis and found reduced myeloid leukocyte infiltration in tumors but not accelerated carcinogenesis compared with wild-type littermates. Our study suggests the feasibility of using exogenous Smad7 below an oncogenic level to alleviate skin inflammation and wound healing defects associated with excessive activation of TGF-beta and NF-kappa B.