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Abstract
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.
Highlights
Traumatic injury, infective-response toxin poisoning, and autoimmune diseases are often accompanied with inflammation [1,2]
Effects of Melatonin on Inflammatory Response Induced by LPS in Intact Goats
The results indicated that MT mainly affects the intracellular membrane structure of peripheral blood mononuclear cells (PBMCs) and influences the formation of lysosomes and their functions
Summary
Infective-response toxin poisoning, and autoimmune diseases are often accompanied with inflammation [1,2]. An excessive inflammatory response results in further tissue and organ damage [3]. When the invading pathogens are detected, various immune cells infiltrate into the infected regions to clean the invaders. Among these immune cells, peripheral blood mononuclear cells (PBMCs) are very important to mediate the inflammatory response [7]. PBMCs accumulate in infected tissues to remove infectious agents and clear dead and injured cells. They closely regulate host defenses, for example, to initiate the inflammatory response locally or systematically [8]. PBMCs repair inflammatorily damaged tissues by secreting various inflammation-mediating cytokines, chemokines, and proteases [11,12,13]
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