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Melatonin suppresses TLR9-triggered proinflammatory cytokine production in macrophages by inhibiting ERK1/2 and AKT activation

Published on Monday, 24 January 2022

Abstract

Toll-like receptor (TLR) signaling plays major roles in innate immune response in macrophages.

Melatonin regulates TLR3- and TLR4-mediated innate immune responses in macrophages. However, it remains unknown whether melatonin regulates TLR9-mediated innate immune responses in macrophages.

Here we demonstrated that melatonin suppressed TLR9 ligand-induced proinflammatory cytokines mRNA and protein production in peritoneal macrophages without interrupting the viability of peritoneal macrophages.

Using a melatonin membrane receptors MT1/MT2 antagonist luzindole, we found that MT1 and MT2 were dispensable for melatonin's inhibitory effects on TLR9-mediated proinflammatory cytokines production, even though melatonin upregulated mRNA expression of MT1 and MT2 in macrophages.

Furthermore, melatonin did not affect mRNA expressions of TLR9 and MyD88 but attenuated TLR9 ligand-induced ERK1/2 and AKT phosphorylation without affecting p38 and NF-κB p65 phosphorylation.

Also, melatonin inhibited TLR9-mediated proinflammatory cytokines production in vivo.

Taken together, our results demonstrate that melatonin suppresses TLR9-triggered proinflammatory cytokines production in macrophages via melatonin membrane receptor-independent manners and probably through inhibiting ERK1/2 and AKT activation, which further elucidates the roles of melatonin in regulating TLR-mediated innate immune responses in macrophages.

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About this publication.

- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);