INTERACTION BETWEEN NUTRIENTS,
PRO-İNFLAMMATORY CYTOKINES
AND INFLAMMATION: NUTRITIONAL MODULATION
--- Assoc. Prof. Dr. H. Tanju BESLER
A B S T R A C T
The p ro -in fla m m a to ry cytokines interleukin 1 & 6 (IL-1 & 6) a n d tıım our necrosis fa c to r (TNF) and fr e e radi- cals ar e relea sed in infection, traııma, cancer and du ring inflam m aiory diseases. F ree radicals and cytoki nes enhance each otlıers production, thereby increasirıg pathological effects. N ııtrients exert w idespread tnodu- latory effects on cytokine biology. Sııboptim al nutrition during p reg n a n cy m ay lea d to lorıg ternı changes in cytokine biology in the offspruıg. D ietary antioxidants (vitamin E a n d catechuıs) a n d precursors o f antioxidant defences (sulphur am ino acids), suppress up-regulation o f cytokine p ro d u ctio n by fr e e radicals. Fats rich in n-3 po lyu n sa tu ra ted fa tty acids (PU FAS) suppress, and fa ts rich in n-6 P U F A s en h a n c e , the production and effects o f IL -1 a nd TNF.
K ey W ords: N ııtrie n ts, a n tio x id a n ts, inflammation, cytokines
Ö Z E T • •
B e s in Ö ğ e le r i S ito k in E tk ile ş im le r i: B e sle n m e M o - d ü la s y o n u
O rganizm am ın ya şa m sa l fa a liyetlerin in devam lılığı, fizyolojik! m et ab olik gereksinm elerinin sağlanması ile m ü m kü n d ü r. Yaşam ın değişik zaman dilimlerinde canlı büyüm e, p la sen ta n ın o lu şu m u , anne siiiü bileşenlerinin sentezi ve organizm aya giren patojenlerin yok edilmesi için gereksinim duyulan m etabolik süreçlerin oluşumu na yö nelm ektedir. İnfeke olrnuş organizm anın yöneldiği temel süreç infeksiyon kaynağı olan patojenin etkis'ız- leştirilm esid ir. Sözü edilen diğer fizyo lo jik süreçler an cak organizm aya giren patojenin etkisizleştirilânesidir. Sözü edilen d iğ er fizy o lo jik süreçler ancak organizma ya giren p a to jen in etkisiz hale getirilm esi ve oluşturdu ğu zararın yok edilm esini takiben yeniden önem kazan maya başlar. B unun nedeni patojenin organizmada üre me kabiliyetinin çok hızlı olm asıdır. Besin öğelerinin oganiztnaya yeterli ve dengeli m iktarlarda sunulması immün sistem fonksiyonlarının düzenli çalışmasına yar dımcı olacaktır. İm m ün sistem fonksiyonlarının
değiş-* Hacettepe University, Department of Nutrition and Dietetics,
mcsi ve metabolik olarak aktivasyonu sonucu, sistemde düzenleyici olarak görev yapan sitokinlerin miktarı art makta ve organizmayı artan besin öğelerinin ihtiyacını karşılamaya yöneltmektedir. Patojenik uyarım sonucu artan sitokin ve serbest radikal düzeyleri patojenin etki sizleştir ilmesine yönelik olmasına rağmen varolan den genin bozulması, organizma açısında son derece zarar lı olabilmektedir. Organizmada oluşan zararın düzeyi, varolan antioksidant savunma sisteminin durumu ile çok yakından ilişkilidir. Antioksidant savunma sistemi nin optimal düzeylerde bulunması patojenik uyarım so nucu oluşabilecek zararlı etkiyi azaltabilecektir. Gerek kalite gereksede kantite açısından sitokin biyolojisi, be sin öğeleri ile yakından ilişkilidir. Vitamin E ve katekin gibi diyette yer alan antioksidantlar ve antioksidant sa vunmada öncü moleküller (kükürtlü amino asitler), ser best radikal uyarısı sonucu artan sitokin üretimini bas- kûamaktadır. n-3 poliunsatiıre yağ asitlerinden zengin yağlar IL 1 ve TNF üretimini ve etkisini baskılarken, n-6 poliunsatüre yağ asitlerinden zengin yağlar arttır maktadır. Yağ asitlerinin var olan bu etkisi inflamatuar hücre membranlarının özelliklerini değiştirmesinden kaynaklandığı ve dolayısıyla bu hücrelerde sitokinlerin etkilerini değiştirdiği düşünülmektedir. Bilimsel verile rin ışığında besin öğeleri ve sitokin etkileşimlerinin bi linmesi klinikte özel durumlarda uygulanan diyetin has talığın klinik seyrinde son derece önemli olduğunu ka nıtlar cimdendir.
A nahtar Sözcükler: Besin öğesi, antioksidantlar, infla- masyon, sitokinler
IN TR O D U C ITO N
Since time immemorial humankind has experienced injury and invasion o f the body by bacteria, viruses, fungi and parasites with the ensuing symptoms o f fe- ver, anorexia, pain and lethargy. Indeed, the fate of empires has hung upon such events. The symptoms are the consequence o f aetivation o f the immune syt- tem by antigenic challenge provided by the invasion. Aetivation of the system results in the release o f pro- inflammatory cytokines, predominantly from pha- gocytic cells, which are widely distributed thougho- ut the body (1-3). Subsecjuently nitrıc oxide hydro- gen peroxide. and superoxide radicals are elicited.
34 BESLER T.
T he production o f cytokines and oxidant m olecules are part o f highly effective m echanism s for creating ah o stile environm ent, w ithin the body, for pathogens (4).
Three pro-inflam m atory cytokines, interleukin I (IL- 1), interleukin 6 (IL-6) and tum our necrosis factor (TNF) orchestrate w idespread m etabolic changes, and mediate and m odulate the enhanced level of ac- tivity of the im m une system .
Cytokines and the metabolic consequences of in- fection
Infection is characterised by w asting o f peripheral tıssues. The w asting, w hich results from loss o f tis sue lıpıd, protein and m icronutrients, is part o f a co- ordınated, cytokine-m ediated response, designed to enhance and support cytokine-m ediated the activities ot the immune system and protect the host.
ino acids release from increase proteolysis in use e, s in and bone, provide substrate for the synthesıs of cells m the system. G lutam ine, released
elucn!TUSC B’ glUCOSe denve from increased hepatic
fin I Of amino aclds and oleıc acjd from
; ~ re7ma)0r sources of nutrıtlon for the
sys-cvntK »,’ “ mC’ 3n lm P ° rtant eofactor in D N A Poratedint1S rCİea.Sed from PeriPheral tıssues,
incor-*»b«q» J» m« “ r !,h!n 1ÎV" "* ki“ney-"4 iîulrîtILI f1*1 ™ F orche*,rat® provide
im m une.system from endogenous tant c UC a Change of nutrient supply is impor-dom mCe an0rexıa’ and 'ethargy are am ong the pre- dom ınant features of infected subjects (8).
The w ıdespread m etabolic changes are designed to deliver nutnents to the im m une system , to assist re- paır o f tıssues, control cytokine production, protect ealthy tıssue from the effects o f free r a d i c a l s and ot- her oxıdant m olecules and rem ove nutrients from the bloodstream w hıch m ight assist m ultiplication o f the pathogen.
Damage to the host from the inflammatory res ponse to pathogens.
Paradoxically, although cytokines play a pivotal role ın the response to infection they can exert tissue da- m aging and lethal effects upon the host. E xcessive, or ınappıopriate production. has been associated with m orbidity and m ortality in a w ide range o f conditions m vvlıich the im m une system has becom e activated. J lıcse in clu d e sepsis. a d u lt re sp ira to ry d istress p d ıo ıııc . m alaria, m eningitis, cystic fibrosis,
syste-m ic lupus e ry th ro syste-m a ts u s , in f la syste-m syste-m a to r y b o w el dise- ase, rh e u m a to id a rth ritis a n d a s th m a (9 -1 2 ). Indeed u n tim ely p ro d u c tio n o f p r o in f la m m a to r y cytokines h av e been im p lic a te d in th e p a th o g e n e s is o f atherosc- lero sis, m u ltip le s c le ro s is a n d A lz h e im e rs disease (1 3 -1 5 ). T h e p o te n tia l fo r d a m a g e to th e h o st is inc reased by a n u m b e r o f b io lo g ic a l e v e n ts vvhich en hance c y to k in e p ro d u c tio n . O x id a n t m o le c u le s upre- gulate c y to k in e p ro d u c tio n b y a c tiv a tio n o f nuclear tran scrip tio n fa c to rs su c h as NFATB a n d N F IL 6 . The factors e n h a n c e tra n s c rip tio n ö f g e n e tic m e ssa g e for ILI and T N F an d IL 6 r e s p e c tiv e ly (1 6 -1 8 ). IL I, IL8 and T N F are p o te n t in d u c e rs o f n itric o x id e an d other o x id an t m o le c u le s fro m p h a g o c y tic c e lls . F u rth e r en- h an cem en t o f c y to k in e p r o d u c tio n m a y o c c u r since ILI and T N F m a y in d u c e p ro d u c tio n o f IL 6 and furt her p ro d u ctio n o f th e m s e lv e s a n d e a c h o th e r.
D am age m ay also b e e x e r te d o n th e h o st by release o f free ra d ic a ls an d o th e r o x id a n t m o le c u le s th at are also rele ased fro m p h a g o c y tic c e lls in re s p o n s e to the in flam m ato ry stim u lu s an d IL I a n d T N F .
Innate system s for reg u la tin g cy to k in e p rod ucti on.
A so p h istic ated array o f c o n tro l s y s te m s e x ist for m o d u latin g c y to k in e p ro d u c tio n an d lim itin g their im pact on the p a tie n t (1 9 ). N a tu ra l in h ib ito rs to ILI and T N F are p ro d u c c d in r e s p o n s e to I LI a n d T N F. Tlıe in h ib ito r for IL I is p ro d u c e d by Iy m p h o cy tes and that fo r T N F is th e e x tr a c e llu la r d o m a in o f T N F recep to rs th a t are sh ed in to th e c irc u la tio n fo llo w in g binding o f T N F to a sm a ll p ro p o rtio n o f re c e p to rs on the surface o f ta rg e t tissu e s. T h e in h ib ito rs are pre- sent in large c o n c e n tra tio n s a n d d o w n re g u la te tissue resp o n siv en ess to th e re sp e c tiv e c y to k in e s . I L I , IL6 and T N F increase the sy n th e sis o f a n u m b e r o f m ole- cıılcs w hich lıave a n tio x id a n t p ro p e rtie s , th e re b y eo- unteracting the ab ility o f o x id a n ts , g e n e ra te d as the co nsequence o f cy to k in e a c tio n , e n h a n c e c y to k in e
p r o d u c t i o n (20). (Jlu c o c o rtic o id s, s e c re te d as a con- sequence o f the action o f IL I and T N F on the hypophyseal adrenal a x is, p lay a k ey ro le in suppres- sing cytokine p ro d u ctio n by en lıa n c iııg lip o co rtin production and stim u latin g a c u te p h a se p ro te in p ro duction (21,22).
Nutritional modulation of cytokine biology.
C ytokines m ay have b e n e fic ia l o r d e trim e n ta l ef fects, depending upon the c o n te x t an d a m o u n ts in w hich they are p ro d u ced . D u rin g in fe c tio n they are m ostly beneficial, in c a n c e r, ch ro n ic in flam m ato ry disease, or in individuals in fe c te d w ith h u m a n im m
u-n odeficieu-ncy v irü s, they m a y be detrim eu-ntal (23). Thus dietary m a n ip u la t io n o f cy to k in e biology can be aim ed at e n h a n c i n g , s u p p re s s in g and controlling cytokine p ro d u c tio n a n d a c tio n s, with potential bene- fıt (4).
Modulation of cytokine biology throughout the li
fe cycle.
It is well a c c e p te d that m a ln u tritio n has m ajör dele- terious effects u p o n i m m u n e function, particularly in the y o u n g and eld e rly . Infants w h o are born small for gectational age e x h ib it r e d u c e d proportions o f circu- lating T cells and im p a ir e d d e la y e d type hypersensi- tivity for a n u m b e r o f y ea rs after birth. In animal mo- dels, g eneral fo o d restrictio n or zinc or vitamin B6 deficiency can im p a ir celi and h u m o ral aspects o f im m unity for se v era l g e n e ra tio n s (see 24 for review) Recent e v id e n c e in a n im a l m o d e ls suggests that p r o g ra m m in g o f the i m m u n e sy ste m by nutrients is also ap p a re n t for p ro -in f la ın m a to ry cytokine biology. Offspring o f rats that w e re fed 12%, 9% or 6% , as opposed to 18% p ro te in d u rin g p re g n a n c y , showed reduced ac u te p h a s e re s p o n s e s to LPS injections in
adulthood. F u r th e r m o r e the a n im als exhibited deran-
ged activity o f key e n z y m e s in the m etabolism of, the antioxidant, g lu ta th io n e (G S H ) (25). Peritoneal mac- rophoges taken fro m adult a n im als, w hose mothers had c o n s u m e d the 9 % casein diet, also show ed an im paired abılıty to p r o d u c e ILI, IL6 and T N F in res- ponse to e n d o to x ın (26).
Modulation of cytokine biology by fats.
İn fla m m a to ry s y m p t o m s are im proved by fish oil or n-3 P U F A s in dise ase s such as rheum atoid arthritis, psoriasis, a s th m a , m u ltip le sc le ro sis,C ro h n ’s disease and ulcerative colitis (27). T h e oil also confers pro- tection in a n im a ls ag a in st the lethal effects o f endo- toxin, burn ınjury and bacterial infection (28-31). y- linolenic acid has also been show n to have a suppres- sıve effect on p la s m a co n c en tratio n s o f a wide range o f cy to k in es (IL I ,IL 2,IL 4,IL 6,T N F & yIF N ) in pati- ents with co lo rec tal c a n c e r (32).
Fats may exert m o d u la to ry effects by influencing the
abilit) ol cells to p ro d u c e cytokines and on the abi-
lity o f target tissues to respond to cytokines. The pro duction and actions o f proinflam m atory cytokines are p ro lo u n d ly influenced by dietary fat intake. This topic has been rev iew e d in detail elsewhere (27,33). In essen ce , tats rich in n-3 polyunsaturated (PUFAs), or n-9 m o n o u n s a tu ra te d fatty acids, or poor in n-6 P U F A s reduce resp o n siv en ess to cytokines (27,34).
Fats rich in n-6 PUFA s exert the opposite effect. Fish oil, which is rich in n-3 PU F A S, reduces the ability o f leukocytes from healthy subjects and rheumatoid
patients to produce E L İ , IL6 and T N F (35). The abi
lity o f peritoneal macrophages from rats to produce ILI and IL6 in response to T N F is greatly influenced by the dietary intake of linoleic acid and total unsa- turated fatty acid intake respectively. ILI production increases to plateau concentrations within a range representing 1-4% of dietary energy, whereas IL6 production is positively related to unsaturated fatty acid intake över a wider range of intakes (36)
An increasing body o f evidence suggests that inapp- ropriate cytokine production may be involved in the development of atherosclerosis (13). Studies on rab- bits show that messenger RN A expression for ILI and T N F in the aorta wall, in response to an endoto- xin injection, is enhanced in by feeding cholesterol in diets containing saturated fat (37).
M any potential mechanisms exist whereby fats may exert their influence upon cytokine biology. The ma-
jority are a c o n s e q u e n c e o f the well docum ented abi
lity of fats to change the fatty acid composition of phospholipids (PL) within the celi membrane. As a cosequence, the fluidity of the celi membrane may change. Alterations in fluidity could, ın turn, change the avidity with which cytokines bind to receptors and the kinetics of conformational change when proteins become activated. Alterations in PL fatty acid composition will change the nature of substrate for the actions o f phospholipase A2 and phospho ıpa se C. Subsequently, modulation of the molecular spe- cies of diacylglycerols and eicosanoids generated when the respective phospholipases are activated will occur. Alterations in the proportions of PL clas ses in the membrane and concentrations of unsatura ted fatty acids within the celi may modulate the actı- vities of enzymes of the protein ldnase C (PKC) fa- mily(36). The extent to which each of these potenti al mechanisms plays a part in the modulatory influ- ences of fats on cytokine biology is at present uncle- ar. M e a s ı ı r e m e n t s of changes in macrophage and he- patocyte membrane fluidity, in response to feeding rats a variety o f fats, suggest that alterations in sensi- tivity of either celi to inflammatory stimuli is not di- rectly due to changes in bulk m em brane fluidity (36).
influence of protein and amino acid intake on
cytokine biology.
Cytokine, acute phase protein and glutathione pro duction is influenced, by the ad eq u acy o f both prote in and sulphur amino acid intake. T h e ability to inc“
36
BESLER T.rease (a -2 -m a c ro g lo b u lin in response to e n d o g e n o u s pyrogen in rabbits, and in response to T N F and tur- pentine abscess in rats, is im paired by low protein di- ets (38-40). In rats given a turpentine abscess, the concentration o f a -2 -m a c ro g lo b u lin increases över a wide range o f protein intakes o f various degrees o f adequacy. The ability o f rats fed low protein diets to increase serum a -l-a c id glycoprotein and hepatic G SH concentrations, in response to T N F is e n h a n ced by dietary supplem entation with glycine and cysteine respectively (391.
W hile cytokines bring about m ajör changes in p ro te in and amino acid m etabolism w hereby am ino acids are released from peripheral tissues for nutrition o f cells of the im m une system and the synthesis o f acu- te phase proteins and glutathione by liver, the supply from the periphery may not always m atch d em ands. There may be an enhanced requirem ent for sulphur and related amino acids following infection and tra- uma (4). Severe traum a and infection cause large decreases in plasm a glycine, serine, and taurine. The- se changes may be due to enhanced utilisation o f a closely related group of amino acids, nam ely glycine, serine and the sulphur amino acids m ethionine and cysteine. M any substances produced in en h a n c e d amount in response to cytokines, are particularly rich ın these amino acids. These substances include g lu tathione, which is com prised o f glycine, glutam ic acid and cysteine, metallothionein, w hich contains o ycine, serine, cysteine and m ethionine to a co m p o - sıte percentage of 56% , and arange o f acute phase proteins which contain up to 25% o f these am ino acı s in their structure. Follow ing surgery o f unin- ected patients, a decrease in the ratio o f urinary sulp- ate to nitrogen occurs, indicating preferential
reten-nc\> SU^ ur amino acids into tissue co m ponents . n studies in rats given T N F , the partitioning o f c> steıne into hepatic protein and glutathione m ay de- pend upon the dietary sulphur amino acid intake. At low levels o f intake, incorporation o f cysteine into protein ıs favoured över incorporation into G S H , at hıgh levels o f intake, the situationis reversed (41). An insufficient intake ofsulphuram ino acids may exert a proinflam m atory influence. In protein deple- ted rats given T N F , en h a n c e m e n to f lung G S H c o n centrations is only possible, if cysteine and m e th io n i ne are added to the diet. Furtherm ore the infıltration of inflam m atory cells into the lung, which occurs in the m alnourished rats in response to the cytokine, is prevcnted by the addition o f sulphur am ino acids to the diet ( 4 1 ). The ability to m aintain and enhance tis sue G S H may be of particular im p o rta n ce in control-
İ1I1L' c y to k in e production in resp o n se to inflam m atory
stim uli, sin c e the s t i m u l a t o r y i n f l u e n c e o f oxidant m o le c u le s a n d T N F , on NFÂTB a c t i v i t y , is decreased by g lu ta th io n e a n d o t h e r s u l p h u r c o n t a i n i n g compo- un d s (4 2 ,4 3 ).
T N F m a y p la y a ro le in the e x t e n s i v e w e i g h t loss ob- se rv e d in p a tie n ts w ith c a n c e r a n d A I D S . It is thus in- teresting to n o te , th a t in a s y m p t o m a t i c H IV - infected in d iv id u a ls , s u b s ta n tia l r e d u c t i o n s in G S H concent rations in p l a s m a a n d l u n g c p i t h e l i a l f lu id o c c u r (44). F u r th e r m o r e the d e c r e a s e in p l a s m a a n d tissu e GSH, o b s e rv e d in A I D S p a t i e n t s , m a y in d i c a t e a require- m e n t for s u lp h u r a m i n o a c id s w h i c h is no t being sa- tisfied by diet o r e n d o g e n o u s s o u r c e s . In such pati ents u rin ary m a l o n a l d e h y d e e x c r e t i o n is e n h a n c e d in dicatin g in c re a s e d fre e r a d ic a l d a m a g e ( 4 5 ,4 6 ) . Alve- olar m a c r o p h a g e s are p r e s e n t in an a c tiv a te d State in such p atien ts a n d e x h i b i t e x a g g e r a t e d p ro d u c tio n of o x id a n ts (47).
P rotein an d a m in o a c id s u p p l e m e n t a t i o n d o not inva- riably p r o d u c e b e n e f it in s i t u a t i o n s vvhich cytokines and in f la m m a to r y a g e n ts are a c t i n g u p o n w ellfed or m a ln o u r i s h e d s u b je c ts . B e n e f i c i a l e f f e c ts on im m une fu n c tio n , m o r b id it y a n d m o r t a l i t y w c r e o b s e rv e d in b u rn e d c h ild re n w h e n a d d i t i o n a l p r o t e i n in the form o f w h e y p ro tein w a s fed . T h e u n s u p p l e m e n t e d and s u p p le m e n t e d diets c o n t a i n e d 16.5 a n d 2 3 % o f ener gy as p ro te in a n d p r o v i d e d 87 a n d 7 3 % o f the energy ı*equirements r e s p e c t i v e l y . I m p r o v e m e n t s in neutrop hil o p s o n ic in d e x , p l a s m a a c u t e p h a s e p r o te in s , sur- vival an d n u m b e r o f d a y s w ith b a c t e r a e m i a w ere no ted in c h ild re n fed the w h e y p r o t e i n su p p le m e n ts (48). In m a l n o u r i s h e d e l d e r l y p a t ie n ts shovving an im p a ire d ability to p r o d u c e c y t o k i n e s , d ie ta ry p ro te in s u p p le m e n t a tio n r e s t o r e d a n d e n h a n c e d pıoducti- on (49). F u r t h e r m o r e a s y m p t o m a t i c in f e c te d m a ln o urished c h ild re n o ften b e c o m e f e b r i le d u r in g nutriti onal r e h a b ilita tio n . T h e a p p e a r a n c e o f f e v e r m a y in dicate an e n h a n c e m e n t o f c y t o k i n e p r o d u c t i o n , previ
ously h e ld in c h e c k by the m a l n o u r i s h e d State (50).
S u ch an e n h a n c e m e n t c a rr ie s b en e fit s as >v ^ 11 as tlan- gers for the h o st if it is n o t p a r t o t a c a r e f u lly coordi n ated m e ta b o lic r e s p o n s e w h i c h d i s a d v a n t a g e s the p ath o g en but p ro te c ts th e h o s t. I n d e e d e n h a n c e d m ortalities h a v e b ee n n o te d in m a l n o u r i s h e d infected p op u latio n s o n c e n u tritio n a l s u p p l e m e n t a t i o n is com - m e n c e d (51). F u r t h e r m o r e , in rats a n o n -le th a l dose o f T N F b e c o m e s lethal if the a b ility of the anim al increase and m a in ta in G S H s y n th e s is is p re v e n te d by adm inistration o f d i e t h y l m a l e a t e (52).
In studies in a n i m a ls , m o r ta lity f r o m m a la r ia and bacterial infection is m o d i f i e d by a lte r a tio n s in
spe-cific a m in o ac id an d p ro tein intake. M ortality in rats from PlasrnodİLim b e r g h e i m a la ria was reduced by low p ro te in diets b u t e n h a n c e d by dietary supple- m e n ta tio n vvith a m ix tu r e o f th reo n in e , valine, leuci- nc and is o le u c in e (53). Likevvise m ortality in guinea pigs, tr o m h s c h e r ic h ia co li and Stcıphylococcııs cıu-
reııs in f e e tio n , w a s in e re a se d fro m 15 to 54% , över a
range o f p ro te in in ta k es fro m an inadequate 5% o f to- tal d ie tary e n e r g y as p r o te in , to 20% o f energy (54). S im ila r d e l e te rio u s effe c ts on m ortality from bactere- m ia w e re o b s c r v e d in g u in e a pigs w hen animals re- c e iv ed in e re a s e d q u a n titie s o f an adequate diet. Whi- le 6 2 % m o r ta lity o c c u r r e d \vhen an adequate quantity vvas fed (125 k c a l/k g /d ) inereasing intake to 150 or 175 k c a l/k g /d r e s u lte d in 100% mortality (55). E n h a n c e d c y t o k in e p r o d u c tio n rather than inereased vi- r u len ce m a y u n d e r ly these paradoxical effects o f di etary s u p p l e m e n t a t i o n .
T h e s e o b s e r v a t io n s s u g g e s t that nutritional strategies c o n c e r n in g the s u p p ly o f a m in o acid substrate to in- d iv id u a ls r e s p o n d i n g to c y to k in e s, should go beyond c o n s id e r a tio n o f ali p ro tein as sim ply being a provi- deı o f p ro te in N , the a m in o acid proportions in that p ro v isio n sh o u ld also be taken into account.
T h e a n o r e x ia in d u c e d by cy to k in es may be an at-te m p t to s e le e tiv e ly a v o id the intake of nutrients w h ich m ig h t d i s a d v a n t a g e the response of the host to p a th o g e n s . I n d e e d , rats given IL1B and a choice of ca-sein, lard o r a m ix tu re o f sucrose and cornstarch, re-d u c e re-d in ta k es o f the protein anre-d fat by 57 & 68% res-p e c tiv e ly , w h e r e a s c a rb o h y d ra te ares-pres-petite was unaf- fected (561.
M odulation of cytokine biology by oxidants and
antioxidant status.
A lte ra tio n s in a n tio x id a n t status may change the in- tensity o f c y to k in e p ro d u c tio n and responses to inf- la m m a t o r y a g e n ts by m o d u la tin g the interaetion bet- w cen tree ra d ic a ls , h y d ro g e n peroxide, and NFATB and N F I L 6 . A e tiv a tio n o f NFATB can be reduced by e n d o g e n o u s a n tio x id a n ts such as glutathione (GSH) and sy n th e tic a n tio x id a n ts such as n-acetyl eysteine. It is u n k n o w n w h e th e r nutrient antioxidants, such as vitam in E, C or 6 -c a ro te n e exert a similar effect. Ho- w c v e r e n h a n c e d p la s m a concentrations o f acute pha- se p ro te in s an d IL 6 w ere ob serv ed in vitamin E defi- cient rats giv e n e n d o to x in (57,58). Cigarette smoking ı aıses p la s m a acute p h a s e protein concentrations sug- g estın g p r o - in f la m m a t o r y cytokine production. Inde- ed blood s a m p le s fro m sm okers contained higher IL6 c o n c e n tr a tio n s than sa m p les from nonsmokers and p r o d u c e d m o re T N F w hen stimulated with
endoto-xin. Vitamin E may modulate cytokine mediated ef fects of smoking as acute phase protein concentrati ons correlated negatively wit vitamin E intake (59). Cellular GSH content is enhanced following exposu- re to cytokines, however the response is dependent upon dietary sufficiency of sulphur amino acid inta ke (41). It is unknown whether an inability to enhan ce GSH in response to cytokines, due a dietary insuf- fıciency of sulphur amino acids, has a pro-inflamma- tory effect. However as indicated earlier inereased numbers of polymorphs were noted in rats which are unable to maintain lung GSH content in response to TN F (41).
Micronutrients are involved in responses to cytokı- nes in a number of roles. These inelude incorporati- on into substances that are synthesised in inereased amounts during inflammation, components of anti- oxidant defences and modulators of immune celi funetion. Trace elements are present in metallothı- onein (Zn), caeruloplasmin (Cu), transferrin (Fe), su- peroxide dismutases (Cu,Se,Zn) and glutathione pe- roxidase (Se).
Copper deficiency, in rats, impairs the ability of rats to inerease plasma caeruloplasmin (CP) and copper- zinc superoxide dismutase in lung, in response to the dual stress of endotoxin injectıon and exposure to high concentrations of oxygen. Likewıse the abı ıty of ILI to inerease plasma concentrations of CP wıt fully functional oxidase activity is also suppressed y copper deficiency (60). Deficiencies in zinc impaır the ability of ILI to induce metalloîhionein synthesıs in rats (61).
iron status may influence the production of cytokı- nes, by its ability to catalyse free radical formatıon. The production of TN F by mice and ILI production by rats, in response to endotoxin, is suppressed y desferrioxamine (an iron ehelator) and by iron e ı ciency respectively (16,62). Furthermore inflamma- tory symptoms,-in rheumatoid arthritis, are exacerba- ted by intravenous iron dextran (63).
C O N C L U S IO N S
The essence of survival, of an individual or species, lies in the ability to prioritise physiological proces- ses, particularly those processeses which exert a lar- ge metabolic demand. Thus at various times throııg- hout the life eyele mammals will focus metabolic processes upon achieving growth, the construction ot placenta and foetus, the synthesis of milk compo- ııents and the combating o f invasion by pathogens. For the infected individual, the m arshalling of
reso-38
BESLER T.urces to co m b at the invading pathogen m u st assum e a priority över ali other physiological events. T h e se other physiological processes can continue once the invasion has been repulsed and the d am ag e done by the invader, repaired. T h e high priority given to com - bating pathogens is necessary because of the speed with which pathogens multiply, once established wit- hin the host. T h e im m u n e system with w hich the in- dividual com bats the invader is likewise capable o f rapid cellular growth. T h e provision o f nutrients to allow the im m une system to function correctly can- not be left to happenstance. T hus cytokines act as modulatory agents by which the activity o f the sy s tem is changed and m etabolic activity o f the host di-
rected tovvards provision of nutrients for the system . The enhanced level o f cytokines and free radical p ro duction which follows pathogenic invasion, although designed to com bat the invader, carries the potential to dam age the host. D am a g e ho w ev er is limited by concurrent eııhancement o f the antioxidant defences of the host and activation o f systems for retaining cytokine production vvithin healthful confines.
As has been discussed earlier, previous and concur- ıent nutrient intake modulate cytokine biology in qu- antitative and qualitative terms s a consequence of the modulation, the host will experience depletion of ıesources and damage which ranges from mild and temporary in nature, to severe, chronic and lethal. The future challenge for the clinician and scientist vvorkıng within the nutrition domain will be in deten- nining how the nature of the nutrient cytokine inte- ıactions, identified in the experimental context, can be em ployed to achieve a healthful diet and clinical benefit (64-66).
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