Melatonin and the Immune System: Roles in Innate and Adaptive Defense

Melatonin is widely recognized for regulating sleep-wake cycles, but it also plays a significant role in immune function. Research indicates that melatonin influences both innate and adaptive immunity, aiding the body’s defense against infections and inflammation. Its effects go beyond sleep regulation, making it an important molecule for overall health.

Understanding its interactions with the immune system provides insight into potential therapeutic applications.

Melatonin Synthesis And Release

Melatonin production is primarily controlled by the pineal gland, a small endocrine structure near the brain’s center. Its synthesis starts with the amino acid tryptophan, which is converted into serotonin. The enzyme arylalkylamine N-acetyltransferase (AANAT) then converts serotonin into N-acetylserotonin, which is subsequently transformed into melatonin by hydroxyindole-O-methyltransferase (HIOMT). This process is tightly regulated by environmental cues, particularly light exposure.

Melatonin release follows a circadian rhythm controlled by the suprachiasmatic nucleus (SCN) of the hypothalamus. During daylight, light exposure suppresses melatonin secretion by inhibiting AANAT activity, keeping levels low. As darkness sets in, the SCN signals the pineal gland to increase production, peaking between 2:00 and 4:00 AM before gradually declining toward morning. Melatonin secretion varies with age—infants produce minimal amounts, adults experience stable nocturnal peaks, and elderly individuals often have reduced levels due to pineal calcification.

Beyond the pineal gland, melatonin is synthesized in peripheral tissues, including the gastrointestinal tract, retina, and bone marrow. Unlike circulating melatonin, which follows a rhythmic pattern, locally produced melatonin functions in a paracrine or autocrine manner, exerting effects within specific tissues. The gastrointestinal tract, for example, contains melatonin concentrations several times higher than in the bloodstream, where it helps regulate digestive processes and protect mucosal integrity.

Role In Innate Immune Response

Melatonin significantly influences the innate immune system, the body’s first line of defense against pathogens. It enhances macrophage activity, stimulating the production of reactive oxygen species (ROS) and nitric oxide (NO), both essential for pathogen destruction. A study in The Journal of Pineal Research found that melatonin-treated macrophages exhibited increased phagocytic activity and an improved ability to eliminate bacterial infections.

Neutrophils, another key component of innate immunity, are also affected by melatonin. These cells respond rapidly to infections, releasing antimicrobial peptides and generating oxidative bursts to eradicate microbes. Melatonin enhances neutrophil chemotaxis—their ability to migrate toward infection sites—by upregulating adhesion molecules such as integrins and selectins. A 2023 meta-analysis in Frontiers in Immunology reported that melatonin supplementation improved neutrophil function in immunocompromised individuals, aiding bacterial and fungal clearance.

Melatonin also modulates natural killer (NK) cell activity, which is crucial for identifying and eliminating virus-infected and cancerous cells. Studies show that melatonin increases NK cell cytotoxicity by promoting the release of perforin and granzyme, proteins that induce apoptosis in target cells. A clinical trial in Cancer Immunology, Immunotherapy found that patients with solid tumors receiving melatonin supplementation had enhanced NK cell activity, correlating with improved immune surveillance and reduced tumor progression.

Inflammatory regulation is another key aspect of melatonin’s role in innate immunity. While inflammation is necessary for pathogen clearance, excessive inflammation can cause tissue damage and chronic disease. Melatonin inhibits nuclear factor-kappa B (NF-κB), a transcription factor that drives the expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). A study in The Lancet Rheumatology found that melatonin reduced systemic inflammation in rheumatoid arthritis patients by downregulating NF-κB signaling, leading to decreased cytokine production and symptom relief.

Role In Adaptive Immune Response

Melatonin influences adaptive immunity by shaping both cellular and humoral responses. It enhances T cell differentiation, guiding naïve T cells into functional subsets such as helper T cells (Th1 and Th2), regulatory T cells (Tregs), and cytotoxic T lymphocytes (CTLs). Research in The Journal of Immunology found that melatonin supplementation increased the expression of transcription factors essential for T cell lineage commitment, suggesting a role in balancing immune responses.

Cytotoxic T lymphocytes, responsible for eliminating virus-infected cells, also benefit from melatonin. Studies show that melatonin enhances CTL proliferation and activation by increasing interleukin-2 (IL-2) production, a cytokine essential for T cell expansion. A controlled trial in Nature Communications found that patients with chronic viral infections who received melatonin exhibited higher CTL activity, leading to improved viral clearance.

Melatonin also supports antibody production by enhancing B cell proliferation and antibody secretion. B cells rely on signaling from helper T cells to mount an effective response. A study in The Lancet Infectious Diseases found that individuals who received melatonin alongside an influenza vaccine had higher serum antibody titers than those who did not, suggesting melatonin may enhance vaccine efficacy. This has sparked interest in its potential to improve immune responses, particularly in older adults with diminished vaccine-induced immunity.

Interactions With Immune Mediators

Melatonin regulates immune function by interacting with cytokines and signaling molecules that coordinate immune activity. It modulates the balance of pro-inflammatory and anti-inflammatory cytokines, influencing interleukins such as IL-1β, IL-6, and IL-10. A study in Cytokine found that melatonin reduced IL-6 levels, which are implicated in chronic inflammation, while increasing IL-10, an immunoregulatory cytokine.

Beyond cytokine modulation, melatonin interacts with transcription factors like NF-κB, which plays a central role in immune activation. Research in Molecular Medicine Reports found that melatonin inhibited NF-κB activation, reducing inflammatory mediator production in autoimmune disorder models. This suggests melatonin’s immunomodulatory effects may help conditions where excessive immune activation contributes to disease progression.