Biology Reference
In-Depth Information
Melatonin receptor activation induces a variety of responses that are mediated both
by pertussis-sensitive and -insensitive G
i
proteins. In the cytoplasm, melatonin inter-
acts with calmodulin
[129]
or tubulin
[130]
. Nuclear receptors of the retinoic acid
receptor superfamily (RZR/ROR ) have been identified in several cells, among
them human lymphocytes and monocytes
[131]
.
The immunomodulatory role of melatonin is related in part to its action on spe-
cific melatonin receptors located in immunocompetent cells. In a study on two human
lymphocytic (Jurkat) and monocytic (U937) cell lines, the addition of melatonin
was found to enhance IL-2 and IL-6 production by acting primarily through nuclear
RZR/ROR receptors
[132]
. Human lymphocyte-synthesized melatonin may play
a crucial role in modulating the IL-2/IL-2 receptor system, as indicated by studies
showing that when melatonin biosynthesis is blocked by the tryptophan hydroxylase
inhibitor parachlorophenylalanine, both IL-2 and IL-2 receptor levels fall, an effect
counteracted by the addition of exogenous melatonin
[131]
. Similarly, prostaglan-
din E
2
-induced inhibition of IL-2 production increased when MT
2
membrane recep-
tors were blocked by luzindole. Taken together, these data indicate that melatonin
synthesized in human lymphocytes is involved in the physiological regulation of the
IL-2/IL-2R expression through a mechanism comprising both membrane and nuclear
melatonin receptors
[131]
.
The contribution of MT
1
and MT
2
receptors in mediating the melatonin-induced
enhancement of cellular and humoral immune function was explored in mice
[133]
. The effect of melatonin-enhanced splenocyte proliferation in both wild-type
and MT
1
/ mice was blocked by the MT
2
antagonist luzindole, indicating that
the melatonin-induced enhancement of immune function was mediated via MT
2
receptors
[133]
.
Repeated stimulation of T helper (Th) cells in the presence of IL-12 causes Th
cells to differentiate into Th1 cells, which produce IL-2 and IFN- and are particu-
larly effective in enhancing immune responses that involve macrophages and other
phagocytes. Melatonin augments IFN- production by Th1 cells. The enhancement
of NK cell activity by melatonin is attributed to the increased production of IL-2 and
IL-12
[131]
. Physiologically, the nocturnal melatonin peak has been associated with
a high IFN-/IL-10 ratio
[134]
. Melatonin's immunoenhancing effect depends on its
ability to enhance the production of cytokines, as well as its antiapoptotic and anti-
oxidant action.
Our studies on the role of melatonin in arthritis have been mainly addressed to
examination of the participation of melatonin in regulation of circadian rhythmicity
of immune parameters in rats
[107]
. Pretreatment for 11 days with a pharmacological
dose of melatonin (100 g) affected some aspects of the early phase of the immune
response elicited by FCA injection, at the preclinical phase of disease. Cell prolif-
eration in rat submaxillary lymph nodes and spleen during the immune reaction (as
assessed by ODC activity) exhibited a pineal-dependent diurnal rhythmicity, as it was
reduced by pinealectomy or pineal sympathetic denervation
[135,136]
. This effect was
counteracted by a pharmacological melatonin dose (100 g/day). Exogenous mela-
tonin also restored the reduced amplitude in diurnal rhythms of lymph node or splenic
tyrosine hydroxylase (TH) activity and lymph node acetylcholine synthesis
[135,136]
.
