AIMS Molecula Science, 3(2): 158-186.
DOI: 10.3934/molsci.2016.2.158
Recei ed 24 Feb ua y 2016,
Accep ed 22 Ap il 2016,
Published 28 Ap il 2016
h p://www.aimsp ess.com/jou nal/Molecula
Re iew
The ole o mela onin in au oimmune and a opic diseases
J.R. Cal o* and M.D. Maldonado
Depa men o Medical Biochemis y, Molecula Biology and Immunology, Uni e si y o Se ille
Medical School, Spain
* Co espondence: Email: [email p o ec ed]; Tel: +34 955421050;
Fax: +34 95 490 7048.
Abs ac : Mela onin is he main sec e o y p oduc syn hesized and sec e ed by he pineal gland du ing
he nigh . Mela onin is a plei opic molecule wi h a wide dis ibu ion wi hin phylogene ically dis an
o ganisms and has a g ea unc ional e sa ili y, including he egula ion o ci cadian and seasonal
hy hms and an ioxidan and an i-in lamma o y p ope ies. I also possesses he capaci y o modula e
immune esponses by egula ion o he TH1/TH2 balance and cy okine p oduc ion. Immune sys em
e adica es in ec ing o ganisms wi hou se ious inju y o hos issues, bu some imes hese esponses
a e inadequa ely con olled, gi ing ise o called hype sensi i i y diseases, o inapp op ia ely a ge ed
o hos issues, causing he au oimmune diseases. In clinical medicine, he hype sensi i i y diseases
include he alle gic o a opic diseases and he hallma ks o hese diseases a e he ac i a ion o TH2
cells and he p oduc ion o IgE an ibody. Rega ding au oimmuni y, a he p esen ime we know ha
he key e en s in he de elopmen o au oimmuni y a e a ailu e o b eakdown o he mechanisms
no mally esponsible o main aining sel - ole ance in B lymphocy es, T lymphocy es, o bo h, he
ecogni ion o sel -an igens by au o eac i e lymphocy es, he ac i a ion o hese cells o p oli e a e
and di e en ia e in o e ec o cells, and he issue inju y caused by he e ec o cells and hei p oduc s.
Mela onin ea men has been in es iga ed in a opic diseases, in se e al animal models o au oimmune
diseases, and has been also e alua ed in clinical au oimmune diseases. This e iew summa izes he
ole o mela onin in a opic diseases (a opic de ma i is and as hma) and in se e al au oimmune diseases,
such as a h i is heuma oid, mul iple scle osis, sys emic lupus e y hema osus, ype 1 diabe es melli us,
and in lamma o y bowel diseases.
Keywo ds: mela onin; au oimmuni y; a opic diseases
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1. In oduc ion
Mela onin (N-ace yl-5-me hoxy yp amine) was disco e ed in 1958 in he bo ine pineal gland by
Le ne and co-wo ke s [1]. Mela onin is he majo sec e o y p oduc syn hesized by his he pineal
gland du ing he nigh and i is he main ch onobio ic ho mone ha egula es he ci cadian hy hms
and seasonal changes in e eb a e physiology ia i s daily noc u nal inc ease in he blood [2,3].
Mela onin is con e ed in wo s eps om he amino acid yp ophan in o se o onin and is hen
ace yla ed by a ylalkylamine N-ace yl ans e ase (EC 2.3.1.87, AANAT), a e which i is con e ed
in o mela onin by hyd oxyndole-O-me hyl ans e ase (EC 2.1.1.4, HIOMT) [4]. Al hough mela onin
was o iginally ecognized as a pineal ho mone, subsequen s udies showed ha his indoleamine
appea ed e y ea ly du ing e olu ion. Thus, mela onin is p esen in bac e ia, unicellula euka yo ic
o ganisms, in e eb a es and e eb a es, algae, plan s and ungi, and is also ound in a ious edibles,
such as ege ables, ui , he bs, and seeds [5,6]. In mammals, mela onin is syn hesized in many issues
and o gans, such as gas oin es inal, espi a o y, geni ou ina y, immune sys ems, and skin [7–13].
Addi ionally, mela onin shows a ema kable unc ional e sa ili y exhibi ing an ioxidan [14–18],
oncos a ic [19,20], an iaging [21,22], and immunomodula o y [11,12,23] e ec s. The molecula
mechanisms esponsible o he pleio opic e ec s o mela onin in ol e mechanisms o ac ion
ecep o -dependen s [24,25] as well as ecep o -independen s [25–28].
A la ge body o e idence has shown a ela ionships be ween ne ous, endoc ine and immune
sys ems and now i is e y clea ha hese sys ems use a common chemical language o in a- and
in e -sys em communica ion [29]. In his amewo k, cu en ly pineal-syn hesized mela onin is
conside ed one o membe s o he complex neu o-endoc ine-immunological ne wo k and he exis ence
o a bidi ec ional communica ion be ween he pineal gland and he immune sys em is comple ely
accep ed [30,31]. Thus, a numbe o in i o and in i o s udies ha e clea ly documen ed ha mela onin
plays a undamen al ole in he unc ion o bo h inna e and immune sys ems [11,12] and a di ec
co ela ion be ween mela onin p oduc ion and he ci cadian and seasonal a ia ions in he immune
sys em has also been documen ed [32,33]. Recip ocally, immunological signals p oduced by he
immunocompe en cells a e pe cei ed by he pineal gland and p o ides a eedback o he egula ion
o pineal unc ion [34–36].
On he o he hand, i is impo an o no e ha cu en ly he skin is conside ed a e y impo an
o gan wi hin o he neu o-endoc ine-immune ne wo k [37,38]. The skin is s a egically loca ed a he
in e ace be ween he ex e nal and in e nal en i onmen whe e de ec s, in eg a es, and esponds o
di e se s esso s and s imuli h ough egula ed p oduc ion o di e en chemical messenge s [38]. Thus,
all o he elemen s con olling he hypo halamus-pi ui a y-ad enal axis, such as co ico opin eleasing
ho mone (CRH), u oco in, and p oopiomelanoco in (POMC)-de i ed neu opep ides, a e exp essed
in he skin [39]. Mo eo e , he skin p oduces many o he p oduc s biologically ac i e, including a
se o onine gic/mela onine gic sys em [40]. In ac , mela onin is syn hesized om se o onin and he
enzyma ic machine y necessa y o he biosyn hesis o mela onin is exp essed in he skin [40,41].
Mo eo e , bo h speci ic ecep o s o se o onin and mela onin a e exp essed in ke a inocy es,
melanocy es, and ib oblas s [42]. In hese cells, mela onin has e ec s on cellula p oli e a ion and
apop osis [43]. Mo eo e , mela onin exe s ecep o -independen e ec s, such as oxida i e s ess p o ec ion
and cellula me abolism modi ica ions [42,44]. Finally, i is impo an o no e ha mela onin is me abolized
in he skin h ough kynu ic and indolic pa hways and he me aboli es p oduced a e 6-hyd oxymela onin,
N(1)-ace yl-N(2)- o myl-5-me hoxykynu amine and 5-me hoxy yp amine [41,45–48]. In his con ex , i
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has been shown ha mela onin and i s me aboli es ha e an ip oli e a i e e ec s on human p ima y
epide mal ke a inocy es and s imula e di e en ia ion in human epide mis, indica ing o ha e an
impo an unc ion in main aining he skin ba ie [46–49].
The molecula basis o he neu oimmunomodula o y e ec o mela onin on he immune sys em is
suppo ed by he exis ence o speci ic mela onin ecep o s in immune o gans as well as in
immunocompe en cells [11,12,50–52]. Thus, hese mela onin ecep o s a e loca ed in plasma memb ane
o he immunocompe en cells. Using adioligands, speci ic binding si es o mela onin ha e been loca ed
and cha ac e ized in plasma memb anes o he se e al ypes o immunocompe en cells o di e en
species including bi ds [53–55], oden s [50,56,57], and human lymphocy es [50,58,59]. Mo eo e and
in human lymphocy es, se e al second messenge s such as cyclic AMP, cyclic GMP, and diacylglice ol,
ha e been in ol ed in he mechanism o ac ion o mela onin in hese cells [60,61]. Finally, i is
impo an o no e ha he classi ica ion and denomina ion o plasma memb ane mela onin ecep o s
ha e been ealized by using he o icial nomencla u e sugges ed by he IUPHAR commi ee [62]. Thus,
he exp ession o wo ypes o plasma memb anes mela onin ecep o s (called MT1 and MT2 ecep o s)
ha e been epo ed in bo h o gans and immune cells o di e en species including human [63–67].
In he con ex o mechanism o ac ion o mela onin, i is impo an o no e ha in he pas he nuclea
ansc ip ion ac o e inoic acid- ela ed o phan ecep o α (RORα), a membe o he o phan nuclea
ecep o amily, was p oposed as he pu a i e nuclea ecep o o mela onin, bu ecen bo h
c ys allog aphy da a and unc ional da a clea ly show ha RORα is a ecep o o choles e ol, s e ols and
secos e oids [68–70]. The e o e, a pu a i e nuclea mela onin ecep o emains o be iden i ied [52].
The immune sys em is unc ionally o ganized in inna e immuni y and adap i e immuni y. Bo h
immune esponses ypes se e he impo an unc ion o hos de ense agains mic obial in ec ions.
No mally, he immune esponse e adica es in ec ing o ganisms wi hou se ious inju y o hos issues.
Howe e , some imes hese esponses a e inadequa ely con olled, gi ing ise o he called hype sensi i i y
diseases, o inapp op ia ely a ge ed o hos issues, causing he au oimmune diseases [71]. The
hype sensi i i y diseases in ol e a pa icula sub ype o T lymphocy e called TH2 cells,
immunoglobulin E (IgE), mas cells, eosinophils, and a a ie y o biochemical media o s. These
media o s collec i ely cause inc eased ascula pe meabili y, asodila ion, and b onchial and isce al
smoo h muscle con ac ion. This eac ion is called immedia e hype sensi i i y because i begins apidly,
wi hin minu es o an igen challenge, and has majo pa hologic consequences. Following he immedia e
esponse, he e is a mo e slowly de eloping in lamma o y componen called he la e-phase eac ion
cha ac e ized by he accumula ion o neu ophils, eosinophils, mac ophages, and CD4+ TH2 cells. This
la e eac ion is igge ed by cy okines p oduced by he TH2 cells and by mas cells, as well as by lipid
media o s sec e ed by mas cells and he e m immedia e hype sensi i i y is commonly used o desc ibe
he combined immedia e and la e-phase eac ions. In clinical medicine, hese eac ions a e called
alle gy o a opy, and he associa ed diseases a e called alle gic, a opic, o immedia e hype sensi i i y
diseases [72,73].
The hallma ks o alle gic o a opic diseases a e he ac i a ion o TH2 cells and he p oduc ion o
IgE an ibody. Repea ed bou s o hese eac ions can lead o ch onic alle gic diseases, wi h issue
damage and emodeling. Alle gic diseases a e he mos common diso de o immuni y, a ec ing 20%
o all indi iduals in he Uni ed S a es. The clinical and pa hologic mani es a ions o immedia e
hype sensi i i y consis o he ascula and smoo h muscle eac ion ha de elops apidly a e epea ed
exposu e o he alle gen and a delayed in lamma o y eac ion. All hese eac ions may be igge ed by
IgE-media ed mas cell ac i a ion, bu di e en media o s a e esponsible o di e en componen s o
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he immedia e and la e-phase eac ions. Immedia e hype sensi i i y eac ions a e mani es ed in
di e en ways, depending on he issues a ec ed, including ashes, sinus conges ion, b onchial
cons ic ion, abdominal pain, dia hea, and sys emic shock [74–77]. In his e iew, we will summa ize
he ole o mela onin in se e al hype sensi i i y diseases, such as a opic de ma i is and as hma.
Rega ding au oimmuni y, we now know ha he key e en s in he de elopmen o au oimmuni y
a e a ailu e o b eakdown o he mechanisms no mally esponsible o main aining sel - ole ance in
B lymphocy es, T lymphocy es, o bo h, he ecogni ion o sel -an igens by au o eac i e lymphocy es,
he ac i a ion o hese cells o p oli e a e and di e en ia e in o e ec o cells, and he issue inju y
caused by he e ec o cells and hei p oduc s [78,79]. Au oimmuni y is an impo an cause o disease
in humans and is es ima ed o a ec 2–5% o he U.S.A. popula ion. Ou unde s anding o
au oimmuni y has imp o ed g ea ly du ing he pas wo decades, mainly because o he de elopmen
o a a ie y o animal models o hese diseases and he iden i ica ion o genes ha may p edispose o
au oimmuni y [80,81]. Ne e heless, he e iology o mos human au oimmune diseases emains
obscu e. Howe e , a he p esen we know ha he majo ac o s ha con ibu e o he de elopmen o
au oimmuni y a e gene ic suscep ibili y and en i onmen al igge s, such as in ec ions. Au oimmune
diseases may be ei he sys emic o o gan speci ic and a ious e ec o mechanisms a e esponsible o
issue inju y in di e en au oimmune diseases [78,82]. This e iew will summa ize he ole o
mela onin in se e al au oimmune diseases, such as a h i is heuma oid, mul iple scle osis, sys emic
lupus e y hema osus, ype 1 diabe es melli us, and in lamma o y bowel diseases.
2. Mela onin and a opic diseases
2.1. A opic de ma i is
A opic de ma i is, also called in Clinical Medicine a opic eczema, is an inc easing common
childhood mul i ac o ial and ch onic in lamma o y skin disease ha also a ec s adul s [83]. The
immunopa hological basis o a opic de ma i is is complex, bu a he p esen ime we know ha i is
media ed by a TH1/TH2 biphasic in lamma o y esponse ha in ol es se e al cy okines, such as IL-4,
IL-5, IL-13 and IFN-γ [84–86]. Rega ding o mela onin and a opic de ma i is, a i s epo shown
e idences o a dys unc ion o he mela onin sec e ion in pa ien s wi h a opic eczema, possibly due o
a pa ially educed ac i i y o he sympa he ic ne ous sys em, which is in ol ed in he con ol o
mela onin sec e ion [87]. La e , i was shown an ele a ion o sali a y mela onin in pa ien s wi h a opic
eczema [88]. By con a y, in he phases o disease ou b eaks i has been documen ed a educ ion in he
se um le els o bo h mela onin and β-endo phin. In he case o mela onin, he di e ence is s a is ically
signi ican only du ing he day, al hough noc u nal le els a e g ea e o bo h ho mones [89]. On he
o he hand, i has been epo ed ha mela onin supp esses he de elopmen o a opic de ma i is-like
skin lesions in 2,4-dini o luo obenzene- ea ed NC/Nga mice by educing o al IgE in se um and IL-
4 and IFN-γ p oduc ion by ac i a ed CD4+ T cells [90]. Mo eo e , i has been shown ha mela onin
inhibi ed he in lamma o y esponse associa ed wi h con ac hype sensi i i y [91] and ha mela onin
ea men a enua ed he delayed- ype hype sensi i i y (DTH) caused by sub-ch onic ea men o
p opoxu in a s [92]. Finally, i has been ecen ly epo ed ha he combined use o del a an and
mela onin a e a ailable o co ec he al e a ion in bo h humo al and cellula immuni y obse ed in an
expe imen al a con ac de ma i is [93].
The po en ial use o mela onin in he ea men o a opic de ma i is has been pos ula ed. In ac ,
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mela onin migh p o ec skin in eg i y ho ough bo h an ioxidan and an iapop o ic e ec s [94–96].
Mo eo e , mela onin migh be in ol ed in he pa hogenesis o a opic de ma i is h ough is egula o y
e ec s on he p oduc ion o se e al cy okines, such as IFN-γ and IL-4. Thus, a ela ionship be ween
IFN-γ, mela onin and a opic de ma i is has been sugges ed [88,97,98] and i has been also pos ula ed
ha mela onin migh educe IgE and IL-4 p oduc ion he eby p e en ing he de elopmen o a opic
de ma i is [90]. On he o he hand, i is known ha sleep dis u bance is e y equen in pa ien s wi h
a opic de ma i is and i has been epo ed ha mela onin supplemen a ion is bo h sa e and e ec i e o
imp o e he sleep-onse la ency [99]. Despi e all abo e men ioned, no clinical ial has in es iga ed
he adminis a ion o mela onin in human a opic de ma i is pa ien s.
2.2. As hma
As hma is a clinical synd ome cha ac e ized by ch onic ai way in lamma ion, ai way
esponsi eness, and expi a o y ai low limi a ion. Mo eo e , pa ien s wi h as hma ha e ci cadian
a ia ions in he ai way in lamma ion and lung unc ion [100]. Bo h noc u nal symp oms and o e nigh
dec eases in lung unc ion a e a common pa o he as hma clinical synd ome and also appea o be
associa ed wi h as hma- ela ed mo ali y [101,102]. A he p esen ime, i is conside ed ha his
disease is de eloped h ough complex in e ac ions be ween gene ic and en i onmen al ac o s and an
imbalance be ween oxida i e s ess and an ioxidan de enses may play a c i ical ole in bo h he
de elopmen and p og ession o disease [103,104]. Cu en ea men s educe as hma ela ed mo ali y,
bu do no modi ies he na u al his o y o he disease [105].
An accumula ing body o e idence sugges s ha mela onin could be in ol ed in he pa hogenesis
o as hma. Thus, in b onchial as hma pa ien s has been ound al e a ions in ci cadian hy hms o
mela onin and co isol [106,107], diso de s in ci cadian hy hm o u ine 6-sulpha oxymela onin (a
mela onin me aboli e) exc e ion [108], and as hma ic pos menopausal women ea ed wi h
glucoco icos e oids showed lowe ed ci cadian sec e ion o mela onin [109]. Mo eo e , in an as hma
clinical pheno ype called aspi in-sensi i e as hma (ASA), i has been shown a lowe le el o 6-
sulpha oxymela onin exc e ion han in aspi in- ole an as hma (ATA) pa ien s [108].
A he p esen ime, i is known ha pla ele s a e in ol ed in he pa hogenesis o b onchial as hma.
P eincuba ion o pla ele - ich plasma wi h mela onin esul ed in an inc ease in bo h he in ensi y and
he a e o he i s pla ele agg ega ion phase in he ASA pa ien s compa ed wi h he ATA pa ien s and
con ol subjec s [110]. In addi ion, in ASA pa ien s has been shown a educed mela onin syn hesis in
pla ele s [111] and a mela onin exp ession in nasal polyps [112]. A ailable clinical da a on ASA
indica e ha ASA pa ien s ha e ce ain dis u bances in he ne ous, endoc ine, immune, and o he
body sys ems. Thus, i has been ound ha such pa ien s ha e a lowe mela onin p oduc ion in day ime,
a pa hology o he pla ele memb ane- ecep o complex, and a pa hological esponse o exogenic
mela onin and ace ylsalicylic acid [113].
Ano he clinical classi ica ion o as hma is noc u nal as hma and non-noc u nal as hma and pa ien s
wi h noc u nal as hma demons a e ci cadian a ia ions in ai way in lamma ion [114]. In his con ex , i
has been epo ed ha mela onin showed di e en ial immunomodula o y e ec s based on as hma clinical
pheno ype (noc u nal and non-noc u nal as hma) [114]. Mo eo e , i has been shown ha ele a ed se um
mela onin is associa ed wi h he noc u nal wo sening o as hma [115]. These esul s sugges ha
mela onin migh play a ole in he pa hogenesis o noc u nal as hma and also may indica e an ad e se
e ec o exogenous mela onin in as hma [114]. The e o e, clinicians should be e y awa e o he

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impo ance o mela onin o noc u nal exace ba ion o as hma symp oms and ale as hma ic pa ien s ha
use exogenous mela onin supplemen a ion could ha e po en ial nega i e e ec s [102].
On he o he hand, i is in e es ing o no e ha i has been ound an inc eased oxida i e s ess in
he exace ba ion pe iod o pa ien s wi h b onchial as hma and ch onic obs uc i e pulmona y disease,
whe eas he an ioxidan enzymes and mela onin we e educed [116,117]. Mo eo e , dis u bed sleep is
common in as hma and i has been epo ed ha mela onin can imp o e sleep in hese pa ien s [118].
As hma is an in lamma o y lung disease cha ac e ized by cell mig a ion, b onchocons ic ion and
hype esponsi eness, and can be induced in expe imen al animals by o albumin (OVA) sensi iza ion
ollowed by a challenge. In his expe imen al model, pinealec omy educed he o al cell numbe
p esen in he lung and bone ma ow cell p oli e a ion, wi hou changing he numbe cells in he bone
ma ow o in he pe iphe al blood [119]. This ac sugges s ha mela onin is impo an in he con ol
o cell ec ui men om he bone ma ow and he mig a ion o hose cells o he lung. Thus, mela onin
adminis a ion o pinealec omized a s seem o es o e he abili y o cells o mig a e om he bone
ma ow o he b onchoal eola luid [119]. Mo eo e , pinealec omy educed he o al in lamma o y
cell numbe in he as hma ic a lung [120]. As consequence, i has been hypo hesized ha mela onin
may modula e he ci cadian in lamma o y a ia ions in as hma by s imula ing he exp ession o
chemo ac ic agen s in he lung epi helial cells. In ac , s udies wi h cul u e lung epi helial cells sugges
ha mela onin migh syne gize wi h p o-in lamma o y cy okines o modula e he as hma ai way
in lamma ion h ough p omo ing he exp ession o chemo axins [120].
Nuclea ac o -kappa B (NF-κB) is a c i ical ansc ip ion ac o go e ning he exp ession o
many cy okines ha a e in ol ed in he pa hogenesis o in lamma o y diseases, such as as hma. In
Sp ague-Dawley a s sensi ized wi h OVA, mela onin inhibi ed he exp ession o NF-κB, down-
egula ed he ac i i y o inducible ni ic oxide syn hase (iNOS) in lung issue and dec eased he
p oduc ion o ni ic oxide (NO) in b onchoal eola la age luid (BALF). These da a sugges ha he
inhibi o y e ec o mela onin p obably play a ole in dec easing ai way hype esponsi eness and
ai way in lamma ion o as hma ic a s models [121]. In addi ion, in a mu ine model o ch onic as hma
i has been desc ibed ha mela onin inhibi ed ai way collagen accumula ion, p obably by he inhibi ion
o me allop o einase-9 [122]. Finally, i is in e es ing o no e ha ano he mechanism which mela onin
may be bene icial in as hma is by egula ing he mucus p oduc ion. Thus, ecen ly i has been shown
ha mela onin inhibi ed mucus p oduc ion in an as hma mu ine model [123].
In summa y and a o he cu en da e, he ole o mela onin in as hma is con o e sial and i is
no clea . Thus, he bene icial e ec s o mela onin would a consequence o i s an ioxidan s p ope ies,
while he nega i e e ec s would a consequence o i s p o-in lamma o y ac i i y [96]. Thus, u he
s udies a e equi ed o in es iga e he long- e m e ec s o mela onin on ai way in lamma ion and
b onchial hype esponsi eness in humans and so o ha e a clea c i e ion o ecommend o no he use
o mela onin in hese pa ien s.
3. Mela onin and au oimmuni y
The e ec s o mela onin on he immune esponse may no always be bene icial. Thus, he e ec s
o mela onin in di e en au oimmune diseases a e no clea , e en some s udies ha e implica ed
mela onin in he de elopmen o di e en au oimmune diseases. Au oimmune diseases a ec
app oxima ely 5% o he popula ion in Wes e n coun ies. These diseases can be sys emic, such as
lupus e y hema osus (SLE), o o gan-speci ic, such as ype 1 diabe es melli us (T1D) [78]. Ou
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unde s anding o au oimmuni y has imp o ed g ea ly du ing he pas wo decades, mainly because o
he de elopmen o a a ie y o animal models o hese diseases and he iden i ica ion o genes ha
may p edispose o au oimmuni y [81,124]. Ne e heless, he e iology o mos human au oimmune
diseases emains obscu e. We now know ha he au oimmuni y esul s om a ailu e o b eakdown o
he mechanisms no mally esponsible o main aining sel - ole ance in B cells, T cells, o bo h and,
consequen ly, he ecogni ion o sel -an igens by au o eac i e lymphocy es, he ac i a ion o hese cells
o p oli e a e and di e en ia e in o e ec o cells, and he issue inju y caused by he e ec o cells and
hei p oduc s [78,79,82].
In his e iew we will ocus he e ec s o mela onin in se e al au oimmune diseases, such as
heuma oid a h i is (RA), mul iple scle osis (MS), sys emic lupus e y hema osus (SLE), ype 1
diabe es (T1D), and in lamma o y bowel disease (IBD).
3.1. Rheuma oid a h i is
Rheuma oid a h i is (RA) is a ch onic in lamma ion o he join s cha ac e ized by p og essi e
e osion o bo h ca ilage and bone ha is associa ed wi h he o ma ion o p oli e a ed pannus. The
pa hogenesis o RA is associa ed wi h hype plasia, inc eased ascula i y, and in il a ion o
in lamma o y immune cells o he syno ial memb ane o he join s. Ac i a ed CD4+ T cells s imula e
monocy es, mac ophages, and syno ial ib oblas s o p oduce di e en in lamma o y cy okines, such
as IL-1β, IL-6, and TNF-α. CD4+ T lymphocy es also s imula e B lymphocy es o p oduce
immunoglobulins [125,126]. The ole o mela onin on RA, a common au oimmune disease su e ed
by app oxima ely 1% o he wo ld’s popula ion [127], is no clea [128,129].
Di e en s udies using expe imen al animal models o a h i is ha e sugges ed dele e ious ac ions
o bo h endogenous and exogenous mela onin. Thus, an ea lie s udy epo ed ha cons an da kness
inc eases he de elopmen o collagen-induced a h i is and exhibi highe i e s o se um an i-collagen
an ibodies han hose kep unde cons an ligh o a no mal pho ope iod [130]. The e ec s o cons an
da kness we e no obse ed in pinealec omized animals [131]. Fu he mo e, adminis a ion o mela onin
o DBA/1 mice immunized wi h a collagen II injec ed subcu aneously and kep unde cons an ligh ,
showed inc eased de elopmen o collagen-induced a h i is (CIA), ia enhancemen o T lymphocy es
p iming, when i was injec ed a he beginning o he immuniza ion, whe eas mela onin injec ion a he
onse o he disease (day 30–39), did no a ec he clinical signs o he disease [132,133]. Ano he s udy
showed ha mela onin inc eased se um an i-collagen an ibody i e and IL-1β and IL-6 le els bo h in
he se um and join s o a h i ic a s, while i dec eased oxida i e ma ke s in se um bu no in join s.
Once mo e, pinealec omy educed an ibodies, cy okine le els and oxida i e s ess in join s, bu also
ele a ed oxida i e ma ke s in se um [134]. Mo eo e , i has been documen ed inc eased noc u nal
pineal p oduc ion o mela onin induced by F eund’s adju an in an expe imen al model o a h i is [135]
and a ecen s udy ound ha mela onin inc eased he se e i y o CIA, p obably ia a enua ion o he
exp ession o c yp och ome 1 [136]. Thus, ac o s ha enhance endogenous mela onin p oduc ion
migh play a ole in he e iology o RA. Howe e and con e sely, in an adju an -induced a h i is in
a s, p ophylac ic and/o he apeu ic ea men wi h mela onin educed hind paw swelling simila o
indome hacin [137]. These con adic o y obse a ions may esul om he di e en dosages u ilized
o di e en expe imen al models used in hese s udies. I is in e es ing o no e ha and ogens ha e
been ound o exe a p o ec i e e ec agains he de elopmen o RA [138]. Thus, i has been shown
ha a Leydig cells exp ess mela onin ecep o s and he sec e ion o es os e one in hese cells was
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educed in he p esence o mela onin [139]. This e ec has been sugges ed o be he cause o he lowe
incidence o RA in men.
I has been shown ha he geog aphical dis ibu ion o RA shows a no h-sou h g adien , wi h highe
la i udes being associa ed wi h an inc eased incidence and se e i y o RA, sugges ing ha augmen ed
mela onin p oduc ion du ing long win e nigh s could be ela ed o RA [140]. Mo eo e , he isk o a h i is
is in e sely associa ed wi h UVB exposi ion [141], which is adia ion known o educe pineal syn hesis o
mela onin [142]. In his con ex , i is impo an o no e ha and addi ional explana ion o incidence o
au oimmune diseases in he No h is lowe p oduc ion o i amin D due o sho age o UVB [143].
Howe e , he e a e UVB immunosupp essi e e ec s independen on he i amin D p oduc ion [144,145].
On he o he hand, i has been epo ed ha he clinical symp oms o RA show a ci cadian a ia ion
wi h join s i ness and pain being mo e p ominen in he ea ly mo ning [146,147], coinciding wi h
high le els o p o-in lamma o y cy okines (especially IL-6 and TNF-α) and low se um concen a ions
o co isol [147–149]. In e es ingly, some au ho s ha e epo ed a ise in blood mela onin le els du ing
he ea ly mo ning in RA pa ien s compa ed wi h heal hy con ols, a posi i e co ela ion be ween
mela onin le els and disease ac i i y sco es, and an ad ance in he noc u nal mela onin peak compa ed
o con ol subjec s [140,147,150]. Howe e , a ecen s udy deno ed ha , al hough mo ning mela onin
se um le els we e highe in RA pa ien s han in heal hy olun ee s, mela onin and RA disease ac i i y
do no co ela e [151]. In his con ex i is possible o specula e ha he highe le els o mela onin in RA
pa ien s migh no be he cause o he symp oms bu as a consequence o he disease, because he RA is
a s esso and he s ess would s imula e he syn hesis o mela onin o p o ec he u he inju y [128,129].
On he o he hand, o he au ho s ha e epo ed signi ican ly lowe le els o mo ning se um mela onin [152]
and e en o he au ho s ha e been obse ed in RA pa ien s ha se um mela onin le els exhibi a wide
pla eau han in heal hy people [153]. I is e y in e es ing o no e ha a clinical ial o mela onin
ea men in RA pa ien s has been conduc ed. In his s udy, pa ien s ecei ed 10 mg mela onin a nigh
o e six mon hs. The e was an inc ease in in lamma o y indica o s, such as neop e in and e y h ocy e
sedimen a ion a es, and low an ioxidan p o iles. Howe e , he e we e no signi ican e ec s on clinical
symp oms o on he le els o TNF-α, IL-1β and IL-6 [154].
Rega ding in i o s udies, i is in e es ing o indica e ha mac ophages in il a ing he syno ial
luid o RA show speci ic mela onin ecep o s [155] and p oduce high le els o IL-12 and NO a e
mela onin adminis a ion [156]. In addi ion, i has been shown ha syno ial luid om RA pa ien s has
ela i ely high le els o mela onin [155] and ha mela onin inhibi s he excessi e p oli e a ion o RA
ib oblas -like syno iocy es h ough ac i a ion o he cyclin-dependen kinase inhibi o s P21 (CIP1) and
P27 (KIP1) media ed by ERK [157]. On he o he hand, syno ial ib oblas s om RA pa ien s show
impai ed ci cadian exp ession o imekeeping genes and p o-in lamma o y cy okines, such as TNF-α,
IL-1β, and IL-6 [158]. Mo e ecen ly, in a s udy wi h human mesenchymal s em cells, i has been shown
ha mela onin signi ican ly educed eac i e oxygen species (ROS) and inc eased supe oxide dismu ase
(SOD) exp ession, es o ed he exp ession o ca ilage ma ix and chond ogenic genes, and p e en ed
he ca ilage deg ada ion by down egula ing ma ix me allop o einases (MMPs) [159].
In summa y, he immuno egula o y and an ioxidan p ope ies o mela onin ha e led scien is o
add ess i s in ol emen in RA. Ne e heless, p elimina y da a sugges s ha he u ili y o mela onin in
he ea men o his disease is ambiguous o nega i e [129,160]. Howe e , i is in e es ing o no e ha
a ecen pape has shown in an expe imen al a model o heuma oid a h i is ha he e ec o
mela onin on se e al hema ologic indices o in lamma ion and immunologic eac i i y was mo e
po en han ha o diclo enac [161].
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3.2. Mul iple scle osis
Ano he se ious au oimmune disease ha migh be ela ed o mela onin is mul iple scle osis (MS).
MS is he mos common in lamma o y demyelina ing disease o he cen al ne ous sys em (CNS) in
young adul s [162], wi h a wo ldwide p e alence o 1.1–2.5 million cases [163]. This disease esul s
om he loss o he neu onal myelin shea h because o a ack by au oan igen-speci ic immune cells.
Bo h adap i e and inna e immune cells, as well as p oin lamma o y cy okines, a e associa ed wi h he
pa hogenesis o MS [164,165]. These cy okines also lead o he gene a ion o ROS in he a ec ed si es
and ma ke s o oxida i e s ess ha e been epo ed in he se a o MS pa ien s [166,167] and in he CNS
o expe imen al animals [168].
An associa ion be ween mela onin and MS has been sugges ed by se e al obse a ions. Thus,
al hough he e iology o MS is no cu en ly ully unde s ood, one en i onmen al ac o ha appea s
o be implica ed is la i ude, so ha sho e win e days could be in ol ed in i s e iology [169–173]. In
addi ion, he p e alence o he disease inc eases in no he n coun ies [174] and a diminished
p e alence has been desc ibed in moun ainous a eas wi h espec o neighbo ing lowe a eas [175].
Fu he mo e, a ecen s udy in es iga ed he ela ionship be ween mela onin pa hway and MS in a
high- isk Finnish popula ion by s udying he single nucleo ide polymo phisms in he genes coding o
enzymes and ecep o s in ol ed in he mela onin pa hway. The esul s o his in es iga ion showed he
associa ion o polymo phisms in he yp ophan hyd oxylases 2 and mela onin ecep o 1B genes wi h
he p og essi e sub ypes o MS and disabili y and sugges a dys egula ion in mela onin pa hway [176].
Finally and in ela ion o he ole o mela onin in he pa hogenesis o MS, epidemiological s udies ha e
hypo hesized a ole o he changes in pineal mela onin sec e ion du ing pube y in he onse o MS [177].
I has been sugges ed a ela ionship be ween an al e ed mela onin ci cadian hy hm and MS. Thus,
shi wo k a a young age has been associa ed wi h inc eased incidence o MS, wi h a posi i e
co ela ion be ween he isk o MS and he du a ion o shi wo k [178]. Mo eo e , i is in e es ing o
no e ha sleep dis up ion is a equen complain in MS pa ien s [179,180]. On he o he hand, MS
pa ien s exhibi impai ed ci cadian hy hms o bo h mela onin and i s ca abolic p oduc , he 6-
sul a oxymela onin. Fu he mo e, a high pe cen age o pa ien s wi h exace ba ed MS we e shown o
display an in e ed mela onin ci cadian hy hm [181] and a lowe o al u ine exc e ion o 6-
sul a oxymela onin han heal hy con ols [182]. Addi ionally, pa ien s exhibi ed signi ican ly educed
nigh - ime exc e ion o 6-sul a oxymela onin when compa ed wi h con ols, which was no malized by
IFN-β ea men [183]. These obse a ions may sugges ha a dys egula ion o physiological le el o
mela onin may be in ol ed in bo h he pa hogenesis and se e i y o MS [160,184,185].
In addi ion o s udies o mela onin ac ion o e he cou se o he MS, endogenous mela onin has
been ela ed o he clinical complica ions o disease. Thus, se um mela onin le els in e sely co ela e
wi h dep ession in MS pa ien s [186]. Addi ionally, diu nal ision impai men ela ed o MS was
shown o be linked o he mela onin ci cadian hy hm and, mo e impo an ly, i was imp o ed by o al
ea men wi h mela onin [187]. On he o he hand, i has been sugges ed a ela ionship be ween
mela onin and he p e alence o seizu es associa ed wi h MS [188]. Despi e e e y hing men ioned
abo e sugges a de imen al e ec o mela onin in MS, o he au ho s ha e ound ha nei he win e -
ype sho days no mela onin supplemen a ion in luence he de elopmen o se e i y o he disease [189].
Mo eo e , o he ecen esea ch sugges s a bene icial ole o mela onin in mul iple scle osis. Thus,
mela onin supplemen a ion in MS pa ien s was a posi i e e ec on se um an ioxidan capaci ies and
imp o ed he quali y o li e o he pa ien s [190]. Mo e ecen ly, i has been epo ed a possible ole o
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