Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed.

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Melatonin: buffering the immune system.

The effects of sex hormones on immune function have received much attention, especially following the proposal of the immunocompetence handicap hypothesis. Many studies, both experimental and correlational, have been conducted to test the relationship between immune function and the sex hormones testosterone in males and oestrogen in females. However, the results are mixed. We conducted four cross-species meta-analyses to investigate the relationship between sex hormones and immune function: (i) the effect of testosterone manipulation on immune function in males, (ii) the correlation between circulating testosterone level and immune function in males, (iii) the effect of oestrogen manipulation on immune function in females, and (iv) the correlation between circulating oestrogen level and immune function in females. The results from the experimental studies showed that testosterone had a medium-sized immunosuppressive effect on immune function. The effect of oestrogen, on the other hand, depended on the immune measure used. Oestrogen suppressed cell-mediated immune function while reducing parasite loads. The overall correlation (meta-analytic relationship) between circulating sex hormone level and immune function was not statistically significant for either testosterone or oestrogen despite the power of meta-analysis. These results suggest that correlational studies have limited value for testing the effects of sex hormones on immune function. We found little evidence of publication bias in the four data sets using indirect tests. There was a weak and positive relationship between year of publication and effect size for experimental studies of testosterone that became non-significant after we controlled for castration and immune measure, suggesting that the temporal trend was due to changes in these moderators over time. Graphical analyses suggest that the temporal trend was due to an increased use of cytokine measures across time. We found substantial heterogeneity in effect sizes, except in correlational studies of testosterone, even after we accounted for the relevant random and fixed factors. In conclusion, our results provide good evidence that testosterone suppresses immune function and that the effect of oestrogen varies depending on the immune measure used.

/pdf/the-effects-of-sex-hormones-on-immune-function-a-meta-2xj7zesym7.pdf

The effects of sex hormones on immune function: a meta-analysis.

The classic theories of aging such as the free radical theory, including its mitochondria-related versions, have largely focused on a few specific processes of senescence. Meanwhile, numerous interconnections have become apparent between age-dependent changes previously thought to proceed more or less independently. Increased damage by free radicals is not only linked to impairments of mitochondrial function, but also to inflammaging as it occurs during immune remodeling and by release of proinflammatory cytokines from mitotically arrested, DNA-damaged cells that exhibit the senescence-associated secretory phenotype (SASP). Among other effects, SASP can cause mutations in stem cells that reduce the capacity for tissue regeneration or, in worst case, lead to cancer stem cells. Oxidative stress has also been shown to promote telomere attrition. Moreover, damage by free radicals is connected to impaired circadian rhythmicity. Another nexus exists between cellular oscillators and metabolic sensing, in particular to the aging-suppressor SIRT1, which acts as an accessory clock protein. Melatonin, being a highly pleiotropic regulator molecule, interacts directly or indirectly with all the processes mentioned. These influences are critically reviewed, with emphasis on data from aged organisms and senescence-accelerated animals. The sometimes-controversial findings obtained either in a nongerontological context or in comparisons of tumor with nontumor cells are discussed in light of evidence obtained in senescent organisms. Although, in mammals, lifetime extension by melatonin has been rarely documented in a fully conclusive way, a support of healthy aging has been observed in rodents and is highly likely in humans.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jpi.12090

Melatonin and the theories of aging: a critical appraisal of melatonin's role in antiaging mechanisms

Circadian rhythms are considered an important factor in the aetiology, expression and treatment of major affective disorders, including seasonal affective disorder (SAD). However, data on the effects of daylight length manipulation or melatonin administration are complex. It has been suggested that since diurnal and nocturnal mammals differ significantly in their physiological and behavioural responses to daylight, diurnal rodents offer a preferable model of disorders related to circadian rhythms in the diurnal human. We previously found that diurnal fat sand rats maintained under short daylight (SD), show depressionlike behaviour in the forced swim test (FST). The present study was designed to test additional behaviours related to affective disorders and study the involvement of melatonin in these behaviours. Sand rats were divided into short-daylight (SD, 5 h light : 19 h dark) and long-daylight (LD, 12 h light : 12 h dark) groups, and received 100 mg melatonin or vehicle administration for 3 wk (5 h and 8.5 h after light onset in the LD room). Animals were then tested for reward-seeking behaviour (saccharin consumption), anxiety (elevated plus-maze), aggression (resident-intruder test), and depression-like behaviour (FST). SD or melatonin administration resulted in a depressed/anxious-like behavioural phenotype including reduced reward seeking, increased anxiety, decreased aggression and decreased activity in the FST, supporting the notion that in a diurnal animal, reduced light results in a variety of behavioural changes that may model depression and anxiety ; and that melatonin may be a significant factor in these changes. We suggest that the sand rat may offer an excellent model species to explore the interactions between daylight, affective behaviour and the related underlying mechanisms.

We are in the dark here: induction of depression- and anxiety-like behaviours in the diurnal fat sand rat, by short daylight or melatonin injections

Tropical field endocrinology: Ecology and evolution of testosterone concentrations in male birds

Seasonal changes in pineal function are well coordinated with seasonal reproductive activity of tropical birds. Further, immunomodulatory property of melatonin is well documented in seasonally breeding animals. Present study elucidates the interaction of peripheral melatonin with seasonal pattern of immunity and reproduction in Indian tropical male bird Perdicula asiatica. Significant seasonal changes were noted in pineal, testicular and immune function(s) of this avian species. Maximum pineal activity along with high immune status was noted during winter month while maximum testicular activity with low immune status was noted in summer. During summer month's long photoperiod suppressed pineal activity and high circulating testosterone suppressed immune parameters, while in winter short photoperiod elevated pineal activity and high circulating melatonin maintained high immune status and suppressed gonadal activity. Therefore, seasonal levels of melatonin act like a major temporal synchronizer to maintain not only the seasonal reproduction but also immune adaptability of this avian species.

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Peripheral melatonin modulates seasonal immunity and reproduction of Indian tropical male bird Perdicula asiatica

Melatonin prevents testosterone-induced suppression of immune parameters and splenocyte proliferation in Indian tropical jungle bush quail, Perdicula asiatica.

Melatonin and differential effect of L-thyroxine on immune system of Indian tropical bird Perdicula asiatica.

Inverse relationship between circulatory levels of glucocorticoids and melatonin has been reported for most of the vertebrates including human beings. We report the importance of glucocorticoid alo...

https://journals.sagepub.com/doi/pdf/10.1177/1721727X1000800206

Effect of Glucocorticoid and Melatonin on Immune Function of an Indian Tropical Bird, Perdicula Asiatica: An in Vivo and in Vitro Study:

Variation in melatonin receptors (Mel1a and Mel1b) and androgen receptor (AR) expression in the spleen of a seasonally breeding bird, Perdicula asiatica

Shiv Shankar Singh

Papers

Peripheral melatonin modulates seasonal immunity and reproduction of Indian tropical male bird Perdicula asiatica

Melatonin prevents testosterone-induced suppression of immune parameters and splenocyte proliferation in Indian tropical jungle bush quail, Perdicula asiatica.

Melatonin and differential effect of L-thyroxine on immune system of Indian tropical bird Perdicula asiatica.

Effect of Glucocorticoid and Melatonin on Immune Function of an Indian Tropical Bird, Perdicula Asiatica: An in Vivo and in Vitro Study:

Variation in melatonin receptors (Mel1a and Mel1b) and androgen receptor (AR) expression in the spleen of a seasonally breeding bird, Perdicula asiatica