Modulation of toll like receptors by naltrexone hydrochloride

• Main Author: Cant, Rachel
• Published: St George's, University of London 2017
• Subjects: 615.1
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.753993

Naltrexone is an opioid antagonist usually used in the treatment of patients addicted to drugs or alcohol. However, since the 1980s naltrexone has been used at lower doses to treat patients with cancer and autoimmune diseases such as multiple sclerosis and Crohn’s disease. The mechanism of action of naltrexone in treating these diseases is unknown, however, evidence suggests that the drug has immune modulating effects. Toll like receptors (TLR) are type I membrane receptors that are crucial in the innate immune response. TLR recognise exogenous and endogenous ligands to induce the production of proinflammatory cytokines, chemokines and activation markers. Recent studies have suggested that naltrexone antagonises TLR4 and TLR9; providing an insight into the immunomodulatory ability of naltrexone. This thesis examines the effect naltrexone has on TLR expressed within the peripheral blood mononuclear cell (PBMC) population with primary focus on TLR 4 and TLR9. In this study, it was observed that naltrexone inhibits IL-6 produced by immune cell subsets following stimulation of TLR2, TLR7 and TLR9, but contrary to previous studies no inhibition of TLR4 was observed. Furthermore, it was determined that apoptosis is not induced under any condition. Studies examining isolated immune cell subsets demonstrated that naltrexone can modulate IL-6 production following stimulation of TLR7/8 on monocytes and TLR9 on B cells. However, naltrexone had no effect on B cell differentiation following stimulation with TLR9 ligand. This study is the first to examine the effect naltrexone has on human immune cells and the findings presented suggest naltrexone has the potential to modulate the production of cytokine in response to TLR activation. Therefore, this study provides preliminary evidence to support the hypothesis that naltrexone modulates TLR activity however, further research is required to justify the use of the drug as an immune modulator in patients with autoimmune diseases and cancer.