Melatonin Rhythms in Mice: Role in Autoimmune and Lymphoproliferative Diseases

Abstract

Production of melatonin (MLT) in the pineal gland (PG) of inbred mice such as C57B1/6J and AKR strains is still a matter of debate. In previous studies, other authors and we showed that these strains of inbred mice have a clear-cut circadian rhythm of serum MLT and urinary 6-hydroxy-MLT-sulfate. In contrast, other groups claimed these mice are unable to synthesize MLT. These studies were based on RIA measurements and/or estimates of N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) activities. In a recent study, we validated the presence of MLT in the PG of C57B1/6, BALB/c, and AKR mice by HPLC determinations. We found a short-term MLT peak in the middle of the dark period with a pattern which mirrors that found previously in the serum. The possibility remains, although it seems unlikely, that the pineal MLT rhythm measured here represents MLT produced elsewhere which is then subsequently taken up by the PG. In the last 15 years we demonstrated that the pineal gland and melatonin (MLT) play an immunoregulatory role both in mice and in humans. In particular we found that MLT: (a) counteracts immunosuppression and thymus atrophy induced by stress or corticosteroid treatment; (b) protects mice injected with encephalitogenic viruses; (c) synergizes with interleukin-2 (IL-2) in cancer immunotherapy; and (d) rescues hematopoiesis from cancer chemotherapy toxicity. Regarding the mechanism of action, MLT seems to act directly on CD4⁺ lymphocytes which release MLT-induced opioid peptides (MIO) with immunoenhancing properties along with other cytokines. These findings prompted us to investigate the role of the pineal gland and MLT in lymphoproliferative and autoimmune diseases. In the first model, C57B16 mice were injected with the leukemogenic virus A-RadLV which induces a murine leukemia type T. Mice were surgically pinealectomized and/or treated with MLT, MLT plus naltrexone, naltrexone alone, and saline. MLT accelerated leukemo- genesis whereas surgical pinealectomy delayed it. Moreover, the action of MLT was blocked by naltrexone indicating the involvement of MIO in the development of lymphomas. In the second study, we investigated the role of the PG and MLT in the immunopathogenesis of autoimmune diabetes mellitus type I, using female non- obese diabetic (NOD) mice as an experimental model. Mice were pinealectomized or treated chronically with MLT (injected subcutaneously or administered via drinking water). We found that neonatal pinealectomy accelerates the development of disease in female NOD mice while exogenous MLT protects animals. This in spite of the fact that MLT increased the production of insulin autoantibodies (IAA). We conclude that the PG and MLT influence the development of autoimmune diabetes although the mechanism of action needs further investigations.