Interleukin-15 based maintenance of metabolic homeostasis and treatment of lung cancer

Abstract

IL-15 is a multifunctional cytokine and plays a key role in activating various types of cells including NK and CD8+ T cells. It also serves as an endocrine involved in the regulation of metabolic homeostasis. The goals of this dissertation study are to demonstrate IL-15 activity in blocking and reversing high-fat diet-induced obesity and obesity-associated metabolic diseases, and to explore its therapeutic potential for treatment of lung cancer metastasized in the liver and kidneys. Gene transfer approach using hydrodynamic-based procedure was employed to achieve over-expression of IL-15 in the form of either IL-15, or IL-15/sIL-15Rα complexes in high-fat diet-fed mice or mice carrying Lewis lung carcinoma. The results show that the method of hydrodynamic gene transfer is effective in delivering Il-15 gene to mouse liver, generating high levels of IL-15 in the blood. An elevated protein level of IL-15 is able to block high-fat diet-induced obesity, insulin resistance, and development of fatty liver. Similarly, transfer of the Il-15/sIl-15Rα gene in obese mice results in reduction of body weight and improvement of insulin sensitivity and glucose homeostasis. The beneficial effects of IL-15 obtained are associated with up-regulation of transcription of genes involving lipolysis in the adipose tissue and skeletal muscle, and decreased mRNA levels of genes responsible for lipogenesis in the liver. Hydrodynamic transfer of the Il-15/sIl-15Rα gene into mice carrying the Lewis lung tumor in the lungs, liver, and kidneys prolongs the survival time of the animals. These results demonstrate the therapeutic potential of IL-15 and provide direct evidence in support of its applications to the treatment of obesity and obesity-associated metabolic diseases, and to lung metastasis in the liver and kidneys.