Curcumin Attenuates Acute Graft-versus-Host Disease Severity via <i>In Vivo</i> Regulations on Th1, Th17 and Regulatory T Cells

<div><p>Background</p><p>In this study we examined the <i>in vivo</i> and <i>in vitro</i> effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model.</p><p>Methodology/Principal Findings</p><p>Mixed lymphocyte reactions were used to determine the <i>in vitro</i> effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4⁺ splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4⁺Foxp3⁺ splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4⁺ regulatory T cells (Tregs) as well as CD8⁺ Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations.</p><p>Conclusion/Significance</p><p>In the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted <i>in vivo</i> preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4⁺ and CD8⁺ Treg) cell lineages as well as B cell homeostasis.</p>