| First Author | Li F | Year | 2019 |
| Journal | J Invest Dermatol | Volume | 139 |
| Issue | 4 | Pages | 940-950 |
| PubMed ID | 30423327 | Mgi Jnum | J:311832 |
| Mgi Id | MGI:6780934 | Doi | 10.1016/j.jid.2018.10.031 |
| Citation | Li F, et al. (2019) Smad7 Ameliorates TGF-beta-Mediated Skin Inflammation and Associated Wound Healing Defects but Not Susceptibility to Experimental Skin Carcinogenesis. J Invest Dermatol 139(4):940-950 |
| abstractText | We assessed the roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGFbeta1/K5.Smad7 bigenic (double transgenic) mice, Smad7 transgene expression reversed transforming growth factor (TGF)-beta1 transgene-induced inflammation, fibrosis, and subsequent epidermal hyperplasia and molecularly abolished TGF-beta and NF-kappaB 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.TGFbeta1 skin. Furthermore, topically applied Tat-Smad7 on K5.TGFbeta1 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-kappaB signaling in K5.TGFbeta1 skin and wounds. Relevant to the clinic, we found that human diabetic wounds had elevated TGF-beta and NF-kappaB 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-kappaB. |
