Figure 2.

The anti-inflammatory effects of melatonin on graft rejection; melatonin commits naïve CD4⁺ cells to T helper type 2 (Th2) cells, which then secrete anti-inflammatory cytokines, including interleukin-10 (IL-10). This induces the generation of IL-10-producing TREG cells, which directly prevent inflammatory processes. The IL-10 inhibits the production of inflammatory cytokines from macrophages, and prevents the normal maturation of dendritic cells (DC). Major histocompatibility complex (MHC) class II expression is also down-regulated on DC, preventing antigen presentation. Melatonin directly reduces graft immunogenicity and damage by preventing mitochondrion-dependent apoptosis. This occurs via the removal of superoxide anions generated during ATP production. Melatonin activates other cell-protective molecules, including glutathione, preventing graft cell apoptosis.