The Immune-Pineal Axis: A Shuttle between Endocrine and Paracrine Melatonin Sources

Abstract

The time course of the innate immunological response involves a pro-inflammatory phase followed by an anti-inflammatory phase. Pro-inflammatory responses serve as a defense against several stressor conditions, and sequential processes that shut down these responses are necessary to avoid exacerbation or the development of chronic diseases. In the present review, we put together recent data that show that the pineal gland is a player in bidirectional control of the inflammatory response. Healthy organisms stay in standby mode, ready to react. The nocturnal melatonin surge impairs the rolling and adherence of leukocytes to endothelial layers, limiting cell migration, and stimulates nocturnal production of IL-2 by T helper lymphocytes, exerting an immunostimulatory effect. Otherwise, the release of TNF-α from activated macrophages suppresses the nocturnal melatonin surge, allowing a full cell migration and inhibiting IL-2 production. In sequence, activated mononuclear and polymorphonuclear cells produce melatonin in a paracrine manner at the site of injury, which scavenges free radicals and collaborates to resolve the inflammatory response. The sequential diminution of TNF-α production is followed by the recovery of the nocturnal melatonin surge and IL-2 production. In summary, the immune-pineal axis, implicated in the sequential involvement of the melatonin produced by the pineal gland and immune-competent cells, is an integral participant of the innate immune response.

Leucocyte Infiltration in Lymphoid Organs and Peritoneal Cavity upon Immunization: Dependence on Circadian Rhythmicity and Melatonin 24-H Profile

“…In turn, leukocyte activation induces the local synthesis of melatonin. Melatonin produced by the activated cells at the site of injury (20) together with cytokine gradient could "help" to keep the cells in the peritoneal cavity. Differently from monocytes and lymphocytes, the number of granulocytes was smaller when the mice were immunized in the morning vs evening.…”

“…Activated macrophages produce also TNF-a. This pro-inflammatory cytokine suppresses nocturnal melatonin production in rat pineal glands, favoring full cell transmigration (20). Thus, the leukocyte migration during the dark time could occur later and might not be so efficient.…”

Age-related changes in melatonin synthesis in rat extrapineal tissues

“…Surprisingly, of the rat extrapineal tissues studied, we have to highlight the results obtained in thymus for thymic mRNA expression and enzyme activity studies as well as the melatonin content measured since these parameters remained unchanged during aging. This could be explained by taking into account the bidirectional communication circuit between pineal melatonin and the immune system (Skwarlo-Sonta et al, 2003;Markus et al, 2007). The pineal gland, via the rhythmic synthesis and release of melatonin, influences the development, differentiation and function of the immune system.…”

The Concept of the Immune-Pineal Axis Tested in Patients Undergoing an Abdominal Hysterectomy

“…The immune-pineal axis was proposed as a working hypothesis to understand the link between the variation in the tissue that synthesizes melatonin and its concentration in the plasma during an innate immune response [1,2]. This transient change in the source of melatonin has important functional implications during the time course of an inflammatory response.…”