Allogeneic skin transplantation is the life-saving therapy for multiple diseases, including extensive burn, large-scale trauma and certain post-surgical complications. However, acute rejection impedes clinical application of allogeneic skin transplantation. Although a lot of novel immunosuppressant drugs have been developed, there is still great need for ideal therapy with less complication and more therapeutic effects. Here, we found interferon gamma (IFN-gamma) as an immunomodulatory cytokine prolonged the survival time of allografts from (8.50 +/- 1.517) days to (14.83 +/- 2.714) days at best. Indoleamine-2, 3-dioxygenase (IDO) has been proposed to play key roles in induction of immune tolerance. Using in vitro tissue culture and primary keratinocytes and fibroblasts, we investigated the regulatory effects of IFN-gamma on the IDO expression. IFN-gamma upregulated IDO expression through STAT3 phosphorylation and this upregulation was reduced by abolition of STAT3 phosphorylation through a STAT3 phosphorylation inhibitor. Interestingly, IFN-gamma induced IDO expression predominately in epidermis rather than dermis. In consistent with these results, IFN-gamma significantly triggered IDO expression in keratinocytes but not fibroblasts. Taken together, this suggests that IFN-gamma might be a potential immunomodulatory drug in acute rejection and keratinocytes in epidermis may play a main role in immune tolerance after allogeneic skin transplantation. (C) 2017 Elsevier Inc. All rights reserved.