THE A C TIO N S OF THE a-M ELANOCYTE
STIM U LATIN G HORM ONE
(a -M S H ) IN IN FLAM M ATO R Y CO N D ITIO N S
Berna K. O kta r, M.Sc. / inci Alican M .D ., Ph.D.
D e p a r t m e n t o f P h y s i o l o g y , S c h o o l o f M e d i c i n e , M a r m a r a U n i v e r s i t y , i s t a n b u l , T u r k e y .
IN TR O DUCTIO N
In fla m m a tio n , a lo c a liz e d re sp o n se to tissue in ju ry , a n d d is o rd e rs c h a ra c te riz e d by in fla m m a tio n are d iffic u lt p ro b le m s in clinical m e dicine. T his d iffic u lty ste m s in large part from in c o m p le te u n d e rs ta n d in g o f in fla m m a to ry p ro c e s s e s a n d th e ir re g u la tio n . R e ce n t d e v e lo p m e n t of th e kn o w le d g e of the role of the c e n tra l n e rv o u s s y s te m a nd n e u ro e n d o c rin e system in the h ost re s p o n s e s has provided a new v ie w of the c a p a c ity of neurona l and soluble m e d ia to rs in th e s e s y s te m s to in flu e n c e in fla m m a tio n . O ne of th e se m e d ia to rs is the e n d o g e n o u s n e u ro p e p tid e a -M S H , w hich is an N -a c e ty l trid e c a p e p tid e d e riv e d fro m the c le a v a g e of a la rg e r p re c u rs o r m olecule, p ro o p io m e la n o c o rtin (P O M C ). It w a s o rig in a lly isolated and ch a ra c te riz e d from the interm ediate lobe of the p itu ita ry and it w a s first recognized by its e ffe c t on s k in m e la n o p h o re s in lo w e r v e rte b ra te s (1).
a -M S H is w id e ly d is trib u te d in tissu e s of higher o rg a n is m s ; it has been id e n tifie d in the pituitary, va rio u s brain regions, skin, circu la tio n and other sites (2). T he p la s m a h alf-life of a -M S H is 20-25 m in in h u m a n s; but its bio lo g ica l half-life is unkn o w n (3). It has been show n th a t plasm a and local a -M S H c o n c e n tra tio n s in cre a se in certain in fla m m a to ry d is o rd e rs and stre ss (2,4). D espite
its s im ila rity in p e p tid e s tru c tu re to a d re n o c o rtic o tro p ic ho rm o n e (A C T H ), a-M S H has no m a jo r in flu e n c e on g lo c o c o rtic o id secretion (5).
Binding sites for the peptide are w id e sp re a d and a -M S H receptors have been ch a ra cte rize d and cloned in va rio u s tissu e s (6,7). T he receptors for a -M S H and related m e la n o co rtin s are specific G p ro te in -c o u p le d re c e p to rs c o n ta in in g seven tra n sm e m b ra n e helixes that activate adenylate cyclase. Five sub typ e s of m elanocortin receptor fam ily have been recognized to date (MC-1 to M C-5). MC-1 re ce p to r is the first receptor that is id e n tifie d on im m u n e /in fla m m a to ry c e lls (8).
C ultured m ouse and hum an m acrophag es and m ela n o cyte s contain m R N A fo r MC-1 receptor (9,10). M C -1, M C -3, M C -4 and M C -5 receptors have been in the brain tissue (11); w hereas, MC-
2 re ce p to r is only found in the adrenal cortex
(1 2). MC-1 is a ls o e x p re s s e d in hum an
n eutroph ils w hich m ay a cco u n t for the inhibitory influence of the peptide on neutrophil m igration in the initial phase of in fla m m a tio n (13).
T here is recent evidence th a t m urine m ast cell line expre sse s m R N A for MC-1 re ceptor and that a -M S H m o d u la te s m a s t cell re s p o n s iv e n e s s (14). In th e s e e x p e rim e n ts , it has been su g geste d that a -M S H m ay e xe rt an inhibitory e ffect on the m ast c e ll-d e p e n d e n t co m p o n e n t of
a s p e c ific in fla m m a to ry re s p o n s e w h ic h is c h a ra c te riz e d by th e re le a s e o f c y to k in e s , ch e m o kin e s and ch e m ica l m e d ia to rs including histam ine and p ro sta g la n d in s.
Anti-inflam m atory Effects of a-M SH in
Anim al Models
In a d d itio n to its w e ll-k n o w n e ffe c t on p ig m e n ta tio n , a -M S H a ls o m e d ia te s o th e r b iologic fu n ctio n s such as co n tro l o f in fla m m a tio n and fe v e r (15). T h e a n ti-in fla m m a to ry and a ntipyretic effe cts of th e p e p tid e are a sso ciated w ith the C O O H -te rm ln a l trip e p tid e se q uen ce, Lys-P ro-V al (a -M S H [11-13]) (16) (F ig.1). a -M S H has a n ti-in fla m m a to ry e ffe cts in all of the m ajor form s of in fla m m a tio n : acute, ch ronic, system ic, a lle rg ic a nd c e n tra l n e rv o u s s y s te m (C N S ) in fla m m a tio n s . T h e e v id e n c e of th e p o te n t influence of a -M S H on a cu te in fla m m a tio n are m o s tly d e riv e d fro m e x p e rim e n ts in w h ic h in fla m m a tio n w a s c a u s e d by in je c tio n of e x o g e n o u s in fla m m a to ry a g e n ts . R e c e n t e v id e n c e o f a n ti-in fla m m a to ry e ffe c t o f the peptide has been o b ta in e d from the e xp e rim e n ts in w h ic h m ice w e re p re tre a te d w ith
C o r y n e b a c te riu m P a r v u m o r b a c te ria l lip o p o lysa cch a rid e (LP S ), a regim en th a t results in severe h e p atitis (17). In this study, a-M S H prevents h e p a tic in jury and in cre a se of p la sm a nitrate / nitrite levels. It also d e c re a s e s LPS- Induced c yto kin e (T N F -a ) and ch e m o k in e (IL -8)
m R N A a c cu m u la tio n and n e u tro p h il infiltration even w hen it is a d m in is te re d 30 m in a fte r LPS challeng e (17).
R e c e n t o b s e rv a tio n s on d e la y e d ty p e h yp e rs e n s itiv ity re a ctio n s in d ica te th a t a-M S H in h ib its in d u ctio n of c o n ta c t h y p e rs e n s itiv ity and leads to h a p te n -s p e c ific to le ra n c e (18). T h ese e ffe cts of a -M S H are p re s u m e d to in vo lve an IL-
1 0 "a n ti-in fla m m a to ry c y to k in e " in te rm e d ia te
b e c a u s e tre a tm e n t w ith th e IL -1 0 a n tib o d y re d u ce s the effe cts of the p e p tid e (18).
a -M S H p re v e n ts d e v e lo p m e n t o f c h ro n ic in fla m m a tio n by in h ib itin g c e llu la r in filtra tio n in a rat m odel of m y c o b a c te riu m -in d u c e d a rth ritis (19). It im p ro v e s several a s p e cts of syste m ic in fla m m a to ry re s p o n s e s y n d ro m e , in c lu d in g w h ite blood cell m igration into the lungs a fte r e n d o to x in 'in fu s io n (20). In a d d itio n , it in cre a se s su rviva l in e x p e rim e n ta l p e rito n itis / e n d o to x e m ia in the rats (2 0).
T he pe p tid e p ro m o te s fu n c tio n a l re co ve ry in C N S isc h e m ia /re p e rfu s io n . R e cent e v id e n c e in dicates that a -M S H m o d u la te s p ro d u c tio n of T N F -a in the brain tissu e of m ice fo llo w in g ce n tra l LPS in je ctio n (21). From th e se o b se rva tio n s, it is cle a r th a t the p e p tid e is e ffe c tiv e in in fla m m a to ry p ro ce sse s th a t o ccu r in w id e s p re a d re g io n s of the body.
It is a ls o re m a rk a b le th a t th e p e p tid e co n c e n tra tio n in c re a s e s in va rio u s c lin ica l and e x p e rim e n ta l in fla m m a to ry d is o rd e rs . T h e co n c e n tra tio n of a -M S H has been d e te rm in e d in synovial tis s u e s and syn o via l fluid of p a tie n ts w ith rh e u m a to id a rth ritis , m y o c a rd ia l in fa rc tio n , e n d o to x e m ia o r H IV in fe c tio n . P e p tid e co n c e n tra tio n ranged from 10' 1 0 and 10- 8 M in
th e s e p a th o lo g ica l c o n d itio n s (22-25). POMC T ACTH a-MSH 1 4 8 11 13
(Ser Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Val)
Mechanisms of the Peripheral Effects
of a-M SH
T he n e u ro p e p tid e a -M S H is im p o rta n t to the natural lim itation of fever, w h ic h is an e a rly host re sp o n se to e n d o to xin . a -M S H give n c e n tra lly or s y s te m ic a lly re d u ce s fe v e r and this in d ica te s th a t the pe p tid e re a ch e s the brain. D uring fe v e r there is p u lsa tile re le a se of the p e p tid e from septal are a s of the brain. a -M S H g ive n e x o g e n o u s ly ca u s e s a n tip y re s is ; w h e re a s b lo c k a d e of the e n d o g e n o u s a -M S H w ith a n tise ru m a u g m e n ts the fe b rile re sp o n se to p y ro g e n s (26).
T h e c a p a c ity o f IL-1 to e lic it a p y ro g e n ic re sp o n se can be e ffe c tiv e ly in h ibited by central a d m in is tra tio n of a -M S H in ra b b its and this s u g g e sts th a t the p e p tid e m ay also be involved in the a ctio n s of IL-1 (27). T h is peptide is a ntipyretic w h e n g iv e n c e n tra lly , in tra v e n o u s ly or in tra g a strica lly. It is 2 5 ,0 0 0 tim es m ore potent than a c e ta m in o p h e n , as an a n ta g o n ist of IL-1 in d uced fe v e r w h e n give n ce n tra lly and 2 0 , 0 0 0
tim e s m ore p o te n t w h e n g iven in tra ve n o u sly (28). R obertson et al. d e m o n s tra te d that intravenous injection o f a -M S H a b ro g a te s fever, neutrophilia and e le va tio n of h e p a tic serum am yloid protein fo llo w e d by in je ctio n of IL-1 (29). In contrast, A C T H is u n a b le to b lo c k e ith e r the neutroph ilia or the serum a m ylo id protein elevation seen in re sp o n se to IL-1, b u t it reduces fe ve r by 67% (29). It has been in d ic a te d th a t the antipyretic action of A C T H is not related to glucocorticoid release b e c a u se A C T H e ffe ctive ly reduces fever in a d re n a le c to m iz e d rabbits (30). Thus, these d a ta in d ica te th a t both A C T H and a -M S H may serve as re g u la to rs of IL-1 related responses in
vivo.
In a d d ition to its action w ith in the brain to reduce fever, a -M S H in h ib its p ro in fla m m a to ry cytokine (e .g ., I L - ip , IL -6 , IF N -y a n d T N F -a )- or
c h e m o a ttra c tiv e c h e m o k in e (e .g ., IL -8
)-d e p e n )-d e n t re a c tio n s both in v itro an)-d in vivo. For exa m p le , it in h ib its T N F -a p roduction by hum an m o n o n u c le a r c e lls an d IF N -y p ro d u c tio n by a n tig e n -s tim u la te d m urine lym ph node cells and pe rip h e ra l b lood m o n o c y te s (31,32). It dow n- re g u la te s the p ro d u ctio n of IFN-y by hum an T ce lls and m o d u la te s IgE s yn th e sis by hum an B ce lls (33). It has bee n sh o w n th a t it com pletely a b o lis h e s m R N A e xp re s s io n fo r IL-8, T N F -a , and
m o n o c y te c h e m o a ttra c ta n t p ro te in- 1 in
e n d o to x in -in d u c e d liv e r in fla m m a to n (17). It also in h ib its the a c tiv a tio n of N F -kB w hich is an im p o rta n t fa c to r fo r th e in d uced tra n scrip tio n of T N F -a (34).
A lth o u g h the m e ch a n is m is not clear, it has been s h o w n th a t a -M S H d o w n -m o d u la te s the tra n s c rip tio n of IL-1 [3, T N F -a b u t not those of IL- 4 and IL-6. C a n n o n et al. found that a -M S H
in h ib its IL -1 -in d u c e d m u rin e th y m o c y te pro life ra tio n and fib ro b la s t PG E p ro duction in
v itro (35). M o re o ve r, the pe p tid e and its a nalog N le 4 -d -P h e 7 -M S H b lo ck re sp o n se s to IL-1 in vivo, but not th y m o c y te p ro liferation
or PGE production stim ulated by IL-1 in vitro (36).
P re v io u s s tu d ie s ha ve sh o w n th a t a -M S H prevents acute inflam m ation a fte r intraderm al injection of LPS, cyto kin e s or irritants including carrageen an and picryl chloride. It prevents LPS- in d u c e d liv e r d a m a g e eve n w h e n it is adm inistered 30 min a fte r LPS (17). It also inhibits IL-1 -, T N F -a -, o r p yro gen-in duced edem a
in v iv o (37). It has show n that plasm a a-M SH concentratio n increases w ithin 1 h follow ing the
peripheral ad m in istra tio n of e n d o g enous pyrogen and this suggests that the peptide is im portant in the early phase of host d efense (38).
S y s te m ic a d m in is tra tio n of th e p e p tid e also re d u c e s s o m e b io lo g ic a l re s p o n s e s of the cytokines and inhibits neutrophil m igration both in
v itro and in vivo. It has been d e m onstrate d that ch e m o ta ctic m igration of hum an n eutroph ils in IL-
8 and N -fo rm y l-m e th io n l-le u c y l-p h e n y la la n in e
(fM LP) g radients w as inhibited by a -M S H in a d o s e -re la te d fa s h io n (13). T h is e ffe c t is pre su m a b ly the result of stim ulation o f MC-1 receptors expressed by neutrophils. How ever, u n like m u rin e and h u m a n m a c ro p h a g e s , neutroph ils are unable to produce either the P O M C -the p re cu rso r of a -M S H - or the peptide itself. A ny influence of a -M S H on neutrophils w ould th e re fo re o ccu r through its paracrine or endocrine a ctions (F ig .2).
M ore recently, it has been d e m onstrate d th a t a - MSH inhibits the p ro duction of nitric oxide (NO) w hich is con sid e re d as a p o tent inflam m atory agent p roduced in large am ounts by m onocytic
F i g .2 s The mechanisms of the effect of a-MSH on macrophages and neutrophils. (Modified from Lipton JM et al. Immunol Today 1997;18:140-145).
cells, p a rtic u la rly m u rin e m a c ro p h a g e s. a -M S H s tim u la te s c A M P p ro d u c tio n a nd in h ib its L P S /cyto kin e -stim u la te d N O and in d u cib le NO synthase (N O S) p ro d u ctio n in m urine and hum an m a crophag es (9). T h e se ce lls have m R N A both fo r the MC-1 re c e p to r and P O M C and they secrete a -M S H w hen stim u la te d w ith T N F -a . a - M SH inhibits L P S -in d u ce d in cre a se s in serum n itrate/nitrite in both LPS and C. P a rv u m /LPS- induced live r injury m o d e ls (17). It also p re ve n ts the induction of i N O S a fte r renal is c h e m ia in m ice and rats (39). R ecently, w e and o th e r in ve stig a to rs have sh o w n th a t a -M S H has a p rotective e ffe ct on c o lo n ic le sio n s in a rat m odel of e xp e rim e n ta l c o litis th ro u g h the in hibition of NO (40). R ajora et al has d e m o n s tra te d th a t a- M SH tre a tm e n t s ig n ific a n tly in h ib its in cre a se d co lo n ic nitrite va lu e s and T N F -a p ro d u ctio n in dextran su lfa te so d iu m -in d u c e d co litis in m ice (41). S im ila rly, a -M S H has been fo u n d to reduce the p ro d u ctio n of N O and T N F -a by cultured m u rin e m ic ro g lia s tim u la te d w ith p -a m y lo id protein in v itro (42).
Mechanisms of fhe Central Effects of
a-MSH
In addition to its a ctio n s w ith in the brain to reduce fever, it is likew ise c le a r th a t a -M S H can act c e n tra lly to in h ib it p e rip h e ra l in fla m m a tio n induced by local a p p lic a tio n of irritants. For exam ple, in the o b s e rv a tio n s of m ice w ith picryl ch loride in d uced e a r in fla m m a tio n , it has been reported th a t ce n tra l a -M S H a d m in is tra tio n - in doses th a t are in e ffe ctive in tra p e rito n e a lly (OH
IO p g )- re d u c e s e d e m a fo rm a tio n (43). S u b se q u e n t stu d ie s have sh o w n th a t central a d m in is tra tio n o f a -M S H a tte n u a te s skin in fla m m a tio n in m ice ca u s e d by in tra d e rm a l injection of the p ro in fla m m a to ry m e d ia to rs such as IL-1P, IL -8 , L T B4 and P A F (44). T h e s e
ob se rva tio n s in d ica te th a t the a n ti-in fla m m a to ry effect of th e p e p tid e in the p e rip h e ry m ay be m ediated by the a -M S H re c e p to rs in the brain. It is cle a r th a t in tact d e s c e n d in g neural pa th w a ys are e ssential to the a n ti-in fla m m a to ry action of ce ntrally a d m in is te re d a -M S H . T ra n s e c tio n o f the spinal cord in m ice w ith hind paw in fla m m a tio n p re ve n ts th e a n ti-in fla m m a to ry a ctio n o f the ce n tra lly a d m in is te re d p e p tid e (45). In addition, in tra p e rito n e a l in je ctio n o f a-M S H in m ice w ith
sp inal tra n s e c tio n has a s m a lle r and d e la ye d a n ti-in fla m m a to ry e ffe c t. By c o n tra s t, a d m in is tra tio n o f the trip e p tid e a - M S H ^ . ^ in the sa m e m odel has strong and rapid in flu e n c e on in fla m m a tio n (45). T h e se o b s e rv a tio n s s u g g e s t th a t the trip e p tid e a - M S H !i_ i3 can act d ire c tly in
the p e rip h e ry to in h ib it in fla m m a tio n w h e re a s, a - M S Hi_i3 p re s u m a b ly re q u ire s th e a ctiv a tio n of
d e s c e n d in g in h ib ito ry p a th w a y s fo r fu ll exp re ssio n of its a n ti-in fla m m a to ry effect.
C e n tra lly a d m in is te re d a -M S H m ust th e re fo re m e d ia te its a n ti-in fla m m a to ry e ffe c ts th ro u g h a ctiva tio n of n e ural p a th w a y s th a t re q u ire s p e cific n e u ro tra n s m itte rs . In th e m o u s e e a r e d e m a m odel, n o n s p e c ific b lo cka d e of the (3-adrenergic re c e p to rs o r s p e c ific b lo c k a d e o f th e (32 -
re c e p to rs in th e p e rip h e ry in h ib its th e a n ti in fla m m a to ry e ffe c t of ce n tra lly a d m in is te re d a - M SH (45). H ow ever, b lo c k a d e o f c h o lin e rg ic (m u sca rin ic) re ce p to rs o r a- or ( $ 1 -a d re n e rg ic
re c e p to rs has no e ffe c t (45). T h e s e re su lts s u g g e s t th a t p e rip h e ra l p2 -a d re n e rg ic n e u ro tra n s m is s io n is e sse n tia l to the e ffe c t of ce n tra l a -M S H on p e rip h e ra l in fla m m a tio n . W ith regard to c h a n g e s in the p e rip h e ra l site of in fla m m a tio n ca u se d by the c e n tra l a -M S H , it is p o ssib le that a -M S H can in h ib it local n e u ro g e n ic c o m p o n e n ts o f the in fla m m a to ry resp o n se . T h a t is, the stim u la tio n of the c e n tra l M C re c e p to rs by th e p e p tid e m ay m o d u la te th e re le a s e of n e u ro g e n ic in fla m m a to ry m e d ia to rs (e .g ., su b s ta n c e P or ca lc ito n in g e n e -re la te d peptide) at the site of in jury a fte r tra n s m is s io n of in h ib ito ry s ig n a ls in th e d e s c e n d in g a n ti-in fla m m a to ry p a th w a y s w h ic h re q u ire th e p re s e n c e of pe rip h e ra l P2 - a d re n e rg ic re ceptors.
CONCLUSION
T he e v id e n ce sited ab o ve in d ica te s th a t a -M S H has p o te n t and broad a n ti-in fla m m a to ry e ffe cts in m a n y fo rm s o f in fla m m a tio n . T h e a n ti in fla m m a to ry a c tio n s of th e p e p tid e th ro u g h the a c tiv a tio n o f c e n tra l a n d /o r p e rip h e ra l m e la n o co rtin re ce p to rs m ig h t be useful in the tre a tm e n t o f so m e c lin ica l c a se s in the future. Low to xicity of the p e p tid e in a n im a ls, its brief d u ra tio n of action and the la ck of e v id e n c e of to le ra n c e to re p e a te d a d m in is tra tio n s u p p o rt fu rth e r in v e s tig a tio n s on the peptide.
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4. R h o rra m O, B e d ra n D e C a s tro JC, M cC ann SM. S tre s s -in d u c e d s e c re tio n o f a a p ro la c tin a n d lu te in iz in g h o r m o n e in th e fe m a le ra t. E n d o c rin o lo g y 1 9 8 5 ,1 1 7 :2 4 8 3 -2 4 8 9 .
5. R o b b a C, R e b u ffa t P, M a z z o c c h i Q, H c u s s d o rfe r OS. L o n g te rm tr o p ic a c tio n s o f a -m e la n o c y te - s tim u la tin g h o rm o n e o n th e z o n a g lo m e ru lo s a o f th e ra t a d re n a l co rte x . A c to E n d o c rin o l 1 9 8 6 ; 1 1 2 :4 0 4 -4 0 8 .
6. C h h a jla n i V, W ikb e rg JES. M o le c u la r c lo n in g a n d e x p re s s io n o f th e h u m a n m e la n o c y te s tim u la tin g h o rm o n e re c e p to r cDTiA. EEBS L e tte r 1 9 9 2 ;3 0 9 :4 1 7 -4 2 0 . 7. G a n tz I, R o n d a Y, T a s h iro T, e t al. M o le c u la r c lo n in g o f a m e la n o c o rtin re c e p to r. J B io l C h e m 1 9 9 3 ;2 6 8 :8 2 4 6 -8 2 5 0 . 8. L ip to n JM , C a ta n ia A. A n ti- in fla m m a to r y a c tio n s o f th e n e u r o im m u n o m o d u la to r a - MSH. Im m u n o l T o d a y 1 9 9 7 ,1 8 : ¡4 0 -1 4 5 . 9. S ta r RA, R a jo ra H, H u a n g J, C h a ve z R, C atania A, L ip to n JM . E v id e n c e o f a u to c r in e m o d u la tio n o f m a c r o p h a g e n it r ic o x id e s y n th a s e b y a -m e la n o c y te - s tim u la tin g h o r m o n e . P ro c H a tl A c a d S c i USA 1 9 9 5 ;9 2 :8 0 1 6 -8 0 2 0 .
10. R a jo ra fi, C e ria n i G, C a ta n ia A, S ta r RA, M u rp h y MT, L ip to n JM . a-M S H p ro d u c tio n , re c e p to rs a n d in flu e n c e o n n e o p te rin in a h u m a n m o n o c y te /m a c ro p h a g e c e ll lin e . J L e u k o c y te B io t 1 9 9 6 :5 9 :2 4 8 -2 5 3 .
11. H o i EM, G is p e n WH, B a r PR. A C T H -related p e p tid e s : re c e p to rs a n d s ig n a l tra n s d u c tio n s y s te m s in v o lv e d in th e ir n e u ro tro p ic a n d n e u r o p r o t e c tiv e a c tio n s . P e p tid e s
1 9 9 5 ,1 6 :9 7 9 -9 9 3 .
12. X ia Y, W ik b e rg JES. In s itu h y b rid iz a tio n h is to c h e m ic a l lo c a liz a tio n o f A CTH re c e p to r mRITA in m o u s e a d re n a l g la n d . C e ll Tissue Res 1 9 9 6 ;2 8 6 :6 3 -6 8 .
13. C a ta n ia A, R a jo ra Ti, C a p s o n i E, M in o n z io E, S ta r RA, L ip to n JM . T he n e u ro p e p tid e a lp h a - MSH has s p e c ific re c e p to rs o n n e u tro p h ils a n d re d u c e s c h e m o ta x is in v itro . P e p tid e s
1 9 9 6 ,1 7 :6 7 5 -6 7 9 .
14. A d a c h i S, H a k a n o T, V lia g o ftis H, M e tc a lfe DD. R e c e p to r-m e d ia te d m o d u la tio n o f m u r in e m a s t c e ll fu n c tio n b y a -m e la n o c y te s tim u la tin g h o rm o n e . J Im m u n o l
1 9 9 9 ; 1 6 3 :3 3 6 3 -3 3 6 8 .
15. L ip to n JM. MSH in CHS c o n tr o l o f fe v e r a n d its in flu e n c e o n in fla m m a t io n /im m u n e re s p o n s e s . In : H a d le y ME, ed. The m e la n o tr o p ic p e p tid e s . B a co R a to n : CRC p re ss, 1 9 8 8 :9 8 -1 1 3 .
16. H iltz ME, L ip to n JM. A n it-in fla m m a to ry a c tiv ity o f a C O O H - te r m in a l fr a g m e n t o f th e n e u ro p e p tid e a-MSH. EASEB J 19 8 9 ;3 :2 2 8 2 - 2 2 8 4 .
17. C h ia o H, P o s te r S, T hom as R, L ip to n J, S ta r RA. a -M e la n o c y te -s tim u la tin g h o rm o n e re d u c e s e n d o to x in - in d u c e d liv e r in fla m m a tio n . J C lin In v e s t 1 9 9 6 :9 7 :2 0 3 8 - 2 0 4 4 .
18. Q ra b b e S, B h a rd w a y RS, M a h n ke R, S im o n MM, S c h w a rz T, L u g e r TA. a -M e la n o c y te - s tim u ia tin g h o rm o n e in d u c e s h a p te n -s p e c ific to le ra n c e in m ice . J Im m u n o l 1 9 9 6 ; 1 5 6 :4 7 3 - 4 7 8 .
19. C e ria n i G, D iaz J, M u rp h re e S, C atania A, L ip to n JM . T he n e u r o p e p tid e a lp h a - m e la n o c y te -s tim u la tin g h o r m o n e in h ib its e x p e r im e n ta l a r h r it is in ra ts. H e u ro im m u n o m o d u la tio n 1 9 9 4 ; 1 -.28-32. 2 0 . L ip to n JM, C e ria n i G, M a ca lu so A, e t al.
A n tiin fla m m a to ry e ffe c ts o f th e n e u ro p e p tid e a -M S H in a c u te , c h ro n ic , a n d s y s te m ic in fla m m a tio n . A n n HY A c a d S c i
1 9 9 4 ;7 4 1 :1 3 7 -1 4 8 .
2 1 . R a jo ra H, B o c c a li G, B u rn s D, S h a rm a S, C a ta n ia AP, L ip to n JM. a-M S H m o d u la te s lo c a l a n d c irc u la tin g tu m o r n e c ro s is fa cto r-a in e x p e rim e n ta l b ra in in fla m m a tio n . J H e u ro s c i
1 9 9 7 ;1 7 :2 1 8 1 -2 1 8 6 .
2 2 . C a ta n ia A, G e rlo n i V, P ro ca ccia S, e t al. The a n tic y to k in e n e u r o p e p tid e a -m e la n o c y te - s tim u la tin g h o rm o n e in s y n o v ia l f lu id o f p a tie n ts w ith rh e u m a tic d ise a se: c o m p a ris o n s
w ith o th e r a n tic y to k in e m o le c u le s . H e u ro im m u n o m o d u la tio n 1 9 9 4 ; 1 -.321 -328. 2 3 . A ira g h i L, L e ttin o M, M a n fre d i MG, L ip to n JM,
C a ta n ia A. E n d o g e n o u s c y to k in e a n ta g o n is ts d u rin g m y o c a rd ia l is c h e m ia a n d th ro m b o ly tic th e ra p y. A m H e a rt J 1 9 9 5 ; 13 0 :2 0 4 -2 1 1 . 2 4 . C a ta n ia A, S u ffre d in i AF, L ip to n JM. E n d o to x in c a u s e s a -M S H re le a s e in n o rm a l h u m a n s u b je c ts . H e u r o im m u n o m o d u la tio n 1 9 9 5 ;2 :2 5 8 -2 6 2 .
2 5 . C a ta n ia A, A ira g h i L, M a n fre d i MG, e t al. P ro o p io m e la n o c o r tin -d e riv e d p e p tid e s a n d
c y to k in e s : re la tio n s in p a tie n ts w ith a c q u ire d im m u n o d e P ic ie n c y s y n d ro m e . C lin Im m u n o l Im m u n o p a th o l 1 9 9 3 ;6 6 :7 3 -7 9 .
2 6 . S h ih ST, R h o rra m O, L ip to n JM , M cC ann SM. C e n tra l a d m in is tra tio n o f a-M S f l a n tis e ru m a u g m e n ts fe v e r in th e ra b b it. A m J P h ysio l
19 8 6 ;2 5 0 :R 8 0 3 -R 8 0 6 .
2 7 . L ip to n JM , G lyn JR. C e n tra l a d m in is tra tio n o f p e p tid e s a lte r th e rm o re g u la tio n in th e ra b b it. P e p tid e s 1 9 8 0 ; 1 :1 5 -1 8 .
2 8 . M u rp h y MT, R ic h a rd s DB, L ip to n JM . A n tip y re tic p o te n c y o f c e n tra lly a d m in is te re d a lp h a - m e la n o c y te - s tim u la tin g h o rm o n e . S c ie n ce 1 9 8 3 ;2 2 1 :1 9 2 -1 9 3 .
2 9 . R o b e rts o n BA, C h a rin g LC, D a y n e s RA. n e u r o p e p tid e r e g u la tio n o f i n t e r le u k in - 1 a c tiv itie s : c a p a c ity o f a - m e la n o c y te s tim u la tin g h o rm o n e to in h ib it in te r le u k in - 1 in d u c ib le re s p o n s e s in v iv o a n d in v itro e x h ib its ta rg e t c e ll s e le c tiv ity . In fla m m a tio n
1 9 8 6 ;1 0 :3 7 1 -3 8 5 .
3 0 . Z im m e r JA , L ip to n JM . C e n tra l a n d p e rip h e ra l in je c tio n s o f A C T fl (1 -2 4 ) re d u c e s fe v e r in a d r e n a le c to m iz e d r a b b its . P e p tid e s
1 9 8 1 ;2 :4 1 3 -4 1 7 .
3 1 . T a y lo r AIV, S tre ile ln JW , C o u s in s S IV. A lp h a - m e la n o c y te -s tim u la tin g h o rm o n e s u p p re s s e s a n tig e n - s tim u la te d T c e ll p r o d u c t io n o f g a m m a -in te rfe ro n . IT e u ro im m u n o m o d u la tio n
1 9 9 4 ;1 :1 8 8 -1 9 4 .
3 2 . L u g e r TA, S c h a u e r E, T ra u tin g e r P. P ro d u c tio n o f im m u n o s u p p re s s in g m e la n o tr o p h in s b y h u m a n k é ra tin o c y te s . A n n riY A c a d S c i 1 9 9 3 ;6 8 0 :5 6 7 -5 7 0 . 3 3 . A e b is c h e r l, S ta m p fli MR, Z u rc h e r A, e t al. n e u r o p e p tid e s a re p o t e n t m o d u la to r s o f h u m a n in v itro im m u n o g lo b u lin E s y n th e s is . E u r J Im m u n o l 1 9 9 4 ;2 4 :1 9 0 8 -1 9 1 3 . 3 4 . M a n n SK, A g g a rw a l BB. a -M e la n o c y te s tim u la tin g h o rm o n e in h ib its th e n u c le a r fa c to r nE -kB a c tiv a tio n in d u c e d b y v a rio u s in fla m m a t o r y a g e n ts . J Im m u n o l
1 9 9 8 ;1 6 1 :2 8 7 3 -2 8 7 7 .
3 5 . C a n n on JG , T a tro JB , R e ic h lin S, D in a re llo CA. A lp h a - m e la n o c y te s t im u la tin g h o r m o n e in h ib its im m u n o s tim u la to r y a n d in fla m m a to ry a c tio n s o f in te r le u k in - 1 . J Im m u n o l
1 9 8 6 ; 13 7 :2 2 3 2 - 2 2 3 6 .
3 6 . D a yn e s RA, R o b e rts o n BA, C h o B, B u rn h a m DR, n e w to n R. A lp h a m e la n o c y te s tim u la tin g h o rm o n e e x h ib its ta rg e t c e ll s e le c tiv ity in its c a p a c ity to a ff e c t in t e r le u k in - 1 in d u c ib le re s p o n s e s in v iv o a n d in v itro . J Im m u n o l
1 9 8 7 ,1 3 9 :1 0 3 -1 0 9 .
3 7 . l i i l t z ME, C a ta n ia A, L ip to n JM . a -M S fl p e p tid e s in h ib it a c u te in fla m m a tio n in d u c e d in m ic e b y r l L - l f i , rlL -6 , rT R F -a a n d e n d o g e n o u s p y ro g e n b u t n o t th a t c a u s e d b y L T B ^, PAP a n d rlL -8 . C y to k in e 1 9 9 2 ;4 :3 2 0 - 3 2 8 . 3 8 . M a rtin LW, D e e te r LB, L ip to n JM. A c u te -p h a s e re s p o n s e to e n d o g e n o u s p y ro g e n in ra b b it: e ffe c ts o f age a n d ro u te o f a d m in is tra tio n . A m J P h y s io l 19 8 9 ;2 5 7-.R 18 9 -R 193.
3 9 . C h ia o fl, R o h d a Y, M c L e ro y P, C raig L, flo u s in i I, S ta r RA. a -M e la n o c y te -s tim u la tin g h o rm o n e p ro te c ts a g a in s t re n a l in ju r y a fte r is c h e m ia in m ic e a n d rats. J C lin In v e s t 1 9 9 7 ; 9 9 : 1 16 5 -
1 1 72.
4 0 . O k ta r BR, E rca n P, Yeğen BÇ, A lic a n i. The e ff e c t o f a lp h a - m e la n o c y te s tim u la tin g h o rm o n e o n c o lo n ic in fla m m a tio n in th e rat. P e p tid e s 2 0 0 0 ;2 1 :1 2 7 1 -1 2 7 7 .
4 1 . R a jo ra R, B o c c o li G, C a ta n ia A, L ip to n JM . a- M S fl m o d u la te s e x p e rim e n ta l in fla m m a to ry b o w e l d isease. P e p tid e s 1 9 9 7 ; 1 8 :3 8 1 -3 8 5 . 4 2 . G a lim b e rti D, B a ro n P, M e d a L, e t al. a -M S fl
p e p tid e s in h ib it p ro d u c tio n o f n itr ic o x id e a n d tu m o r n e c ro s is fa c to r-a b y m ic ro g lia l c e lls a c tiv a te d w ith [5-a m y lo id a n d in te rfe ro n y . B io c h e m B io p h y s R es C o m m u n
1 9 9 9 ;2 6 3 :2 5 1 -2 5 6 .
4 3 . L ip to n JM , M a c a lu s o A, f l i lt z ME, C a ta n ia A. C e n tra l a d m in is tra tio n o f th e p e p tid e a -M S fl in h ib its in fla m m a tio n in th e s k in . P e p tid e s
1 9 9 1 ;1 2 :7 9 5 -7 9 8 .
4 4 . C e ria n i G, M a c a lu s o A, C a ta n ia A, L ip to n JM. C e n tra l n e u ro g e n ic a n tiin fla m m a to r y a c tio n o f a -M S H : m o d u la tio n o f p e r ip h e r a l in fla m m a tio n in d u c e d b y c y to k in e s a n d o th e r m e d ia to r s o f in fla m m a t io n . R e u ro e n d o c rin o lo g y 1 9 9 4 ;5 9 : 1 3 8 - 14 3 . 4 5 . M a c a lu s o A, M c C o y D, C e ria n i G, e t al. A n tiin f la m m a to r y in flu e n c e s o f a -M S fl m o le c u le s : c e n tra l n e u ro g e n ic a n d p e rip h e ra l a c tio n s . J R e u ro s c i 1 9 9 4 ;1 4 :2 3 7 7 -2 3 8 2 .
