| Summary: | The anti-inflammatory activity of melatonin (MT) has been well documented; however, little is known regarding endogenously occurring MT in this respect, especially for large animals. In the current study, we created a MT-enriched animal model (goats) overexpressing the MT synthetase gene Aanat. The responses of these animals to lipopolysaccharide (LPS) stimulation were systematically studied. It was found that LPS treatment exacerbated the inflammatory response in wild-type (WT) goats and increased their temperature to 40 °C. In addition, their granulocyte counts were also significantly elevated. In contrast, these symptoms were not observed in transgenic goats with LPS treatment. The rescue study with MT injection into WT goats who were treated with LPS confirmed that the protective effects in transgenic goats against LPS were attributed to a high level of endogenously produced MT. The proteomic analysis in the peripheral blood mononuclear cells (PBMCs) isolated from the transgenic animals uncovered several potential mechanisms. MT suppressed the lysosome formation as well as its function by downregulation of the lysosome-associated genes Lysosome-associated membrane protein 2 (LAMP2), Insulin-like growth factor 2 receptor (IGF2R), and Arylsulfatase B (ARSB). A high level of MT enhanced the antioxidant capacity of these cells to reduce the cell apoptosis induced by the LPS. In addition, the results also uncovered previously unknown information that showed that MT may have protective effects on some human diseases, including tuberculosis, bladder cancer, and rheumatoid arthritis, by downregulation of these disease-associated genes. All these observations warranted further investigations.
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