Prostaglandins and proinflammatory cytokines are implicated in the etiology of neurodegenerative diseases, such as Alzheimer's disease. Signaling cascades initiated by these factors may result in reactive oxygen species generation and cell death. The insulin-like growth factors (IGF) are ubiquitous polypeptides involved in all aspects of growth and development. Additionally, the IGF are regarded as survival factors that display potent antiapoptotic activity. Interfering with IGF production, distribution, or signaling may result in greater susceptibility to apoptotic stimuli. In neurodegenerative conditions, the IGF appear to be antagonized by prostaglandins and proinflammatory cytokines. In this review, the relationship among specific prostaglandins, the proinflammatory factors, tumor necrosis factor, interleukin-1, and interleukin-6, and the IGF system will be investigated.
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References
1.
HorsburghK, SaitohT.Altered signal transduction in Alzheimer's disease. In: TerryRD, KatzmanR, BickKL Eds. Alzheimer's Disease. New York: Raven Press, pp 387–404, 1994.
2.
SagaraY, DarguschR, ChambersD, DavisJ, SchubertD, MaherP.Cellular mechanisms of resistance to chronic oxidative stress. Free Radic Biol Med24: 1375–1389, 1998.
3.
KellerJN, GuoQ, HoltsbergFW, Bruce-KellerAJ, MattsonMP. Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. J Neurosci18: 4439–4450, 1998.
4.
GitterBD, CoxLM, RydelRE, MayPC. Amyloid β peptide potentiates cytokine secretion by interleukin-1 β-activated human astrocytoma cells. Proc Natl Acad Sci U S A92: 10738–10741, 1995.
5.
HornJT, EstridgeT, PechousP, HyslopPA. The amyloidogenic peptide human amylin augments the inflammatory activities of eosinophils. J Leukoc Biol58: 526–532, 1995.
6.
BruggB, DubreuilYL, HuberG, WollmanEE, Delhaye-BouchaudN, MarianiJ.Inflammatory processes induce β-amyloid precursor protein changes in mouse brain. Proc Natl Acad Sci U S A92: 3032–3035, 1995.
7.
BaskinF, SmithGM, FosmireJA, RosenbergRN. Altered apolipo-protein E secretion in cytokine-treated human astrocyte cultures. J Neurol Sci148: 15–18, 1997.
8.
DashPK, MooreAN. Enhanced processing of APP induced by IL-1β can be reduced by indomethacin and nordihydroguaiaretic acid. Biochem Biophys Res Commun208: 542–548, 1995.
9.
GrilliM, GoffiF, MemoM, SpanoP.Interleukin-1β and glutamate activate the NF-κB/Rel binding site from the regulatory region of the amyloid precursor protein gene in primary neuronal cultures. J Biol Chem271: 15002–15007, 1996.
10.
McGeerPL, RogersJ.Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology42: 447–449, 1992.
11.
SubbaramaiahK, ZakimD, WekslerBB, DannenbergAJ. Inhibition of cycoloxygenase: A novel approach to cancer prevention. Proc Soc Exp Biol Med216: 201–210, 1997.
12.
PasinettiGM, AisenPS. Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain. Neuroscience87: 319–324, 1998.
13.
PrasadKN, HowlandAR, La RosaFG, HowlandPG. Prostaglandins as putative neurotoxins in Alzheimer's disease. Proc Soc Exp Biol Med219: 120–125, 1998.
14.
GrilliM, PizziM, MemoM, SpanoPF. Neuroprotection by aspirin and sodium salicylate through blockade of NF-κB activation. Science274: 1383–1385, 1996.
15.
D'ErcoleAJ, YeP, CalikogluAS, Gutierrez-OspinaG.The role of insulin-like growth factors in the central nervous system. Mol Neurobiol13: 227–255, 1996.
16.
DoréS, KarS, QuirionR.Rediscovering an old friend, IGF-1: potential use in the treatment of neurodegenerative diseases. Trends Neurosci20: 326–331, 1997.
17.
PruzanskiW, StefanskiE, VadasP, KennedyBP, van den BoschH.Regulation of the cellular expression of secretory and cytosolic phospholipases A2, and cyclooxygenase-2 by peptide growth factors. Biochim Biophys Acta1403: 47–56, 1998.
18.
FiebichBL, HullM, LiebK, SchumannG, BergerM, BauerJ.Potential link between interleukin-6 and arachidonic acid metabolism in Alzheimer's disease. J Neural Transm Supplement54: 268–278, 1998.
19.
OkaA, ItohM, TakashimaS.The early induction of cyclooxygenase-2 associated with neurofibrillary degeneration in brains of patients with Fukuyama-type congenital muscular dystrophy. Neuropediatrics30: 34–37, 1999.
20.
LeeRK, KnappS, WurtmanRJ. Prostaglandin E2 stimulates amyloid precursor protein gene expression: Inhibition by immunosuppressants. J Neurosci19: 940–947, 1999.
21.
LicastroF, DavisLJ, PedriniS, GalaskoD, MasliahE.Prostaglandin E2 induced polymerization of human α-1-antichymotrypsin and suppressed its protease inhibitory activity: Implications for Alzheimer's disease. Biochem Biophys Res Commun249: 182–186, 1998.
22.
RechlerMM. Insulin-like growth factor binding proteins. Vitam Horm47: 1–114, 1993.
23.
Di BattistaJA, DoréS, MorinN, HeY, PelletierJP, Martel-PelletierJ.Prostaglandin E2 stimulates insulin-like growth factor binding protein-4 expression and synthesis in cultured human articular chondrocytes: Possible mediation by Ca++-calmodulin regulated processes. J Cell Biochem65: 408–119, 1997.
24.
PashJM, CanalisE.Transcriptional regulation of insulin-like growth factor-binding protein-5 by prostaglandin E2 in osteoblast cells. Endocrinology37: 2375–2382, 1996.
25.
BuiT, StrausDS. Effects of cyclopentenone prostaglandins and related compounds on insulin-like growth factor-1 and Waf1 gene expression. Biochim Biophys Acta1397: 31–42, 1998.
26.
MontineTJ, MarkesberyWR, MorrowJD, RobertsLJII. Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer's disease. Ann Neurol44: 410–413, 1998.
27.
Castilla-CortazarI, GarciaM, MuguerzaB, QuirogaJ, PerezR, SantidrianS, PrietoJ.Hepatoprotective effects of insulin-like growth factor 1 in rats with carbon tetrachloride-induced cirrhosis. Gastroenterology113: 1682–1691, 1997.
28.
PattersonPH. Cytokines in Alzheimer's disease and multiple sclerosis. Curr Opin Neurobiol5: 642–646, 1995.
29.
FinchCE, CohenDM. Aging, metabolism, and Alzheimer disease: Review and Hypotheses. Exp Neurol143: 82–102, 1997.
30.
FeghaliCA, WrightTM. Cytokines in acute and chronic inflammation. Front Biosci2: 12–26, 1997.
31.
LiebK, FiebichBL, SchallerH, BergerM, BauerJ.Interleukin-1β and tumor necrosis factor-a induce expression of α1-antichymotrypsin in human astrocytoma cells by activation of nuclear factor-κB. J Neurochem67: 2039–2044, 1996.
32.
LanzreinAS, JohnstonCM, PerryVH, JobstKA, KingEM, SmithAD. Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: Interleukin-1b, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-α, the soluble tumor necrosis factor receptors I and II, and α1-antichymotrypsin. Alzheimer Dis Assoc Disord12: 215–227, 1998.
33.
ShengJG, ItoK, SkinnerRD, MrakRE, RovnaghiCR, Van EldikLJ, GriffinWS. In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurobiol Aging17: 761–766, 1996.
34.
AlvarezXA, FrancoA, Fernandez-NovoaL, CacabelosR.Blood levels of histamine, IL-1 β, and TNF-α in patients with mild to moderate Alzheimer's disease. Mol Chem Neuropathol29: 237–252, 1996.
35.
StroemerRP, RothwellNJ. Exacerbation of ischemic brain damage by localized striatal injection in interleukin-1β in the rat. J Cereb Blood Flow Metab18: 833–839, 1998.
36.
YangGY, GongC, QinZ, YeW, MaoY, BertzAL. Inhibition of TNF-α attenuates infarct volume and ICAM-1 expression in ischemic mouse brain. Neuroreport9: 2131–2134, 1998.
37.
PanW, ZadinaJE, HarlanRE, WeberJT, BanksWA, KastinAJ. Tumor necrosis factor-α: A neuromodulator in the CNS. Neurosci Biobehav Rev21: 603–615, 1997.
38.
Lezoualc'hF, BehlC.Transcription factor NF-κB: Friend or foe of neurons?Mol Psychiatry3: 15–20, 1998.
39.
BlaskoI, SchmittTL, SteinerE, TriebK, Grubeck-LoebensteinB.Tumor necrosis factor-α augments amyloid β protein (25–35)-induced apoptosis in human cells. Neurosci Lett238: 17–20, 1997.
AloeL, FioreM, ProbertL, TurriniP, TirassaP.Overexpression of tumour necrosis factor-α in the brain of transgenic mice differentially alters nerve growth factor levels and choline acetyltransferase activity. Cytokine11: 45–54, 1999.
42.
McLayRN, FreemanSM, HarlanRE, IdeCF, KastinAJ, ZadinaJE. Aging in the hippocampus: Interrelated actions of neurotrophins and glucocorticoids. Neurosci Biobehav Rev21: 615–629, 1997.
43.
VirginCEJr.., HaTP, PackanDR, TombaughGC, YangSH, HornerHC, SapolskyRM. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: Implications for glucocorticoid neurotoxicity. J Neurochem57: 1422–1428, 1991.
44.
BitarMS. Glucocorticoid dynamics and impaired wound healing in diabetes mellitus. Am J Pathol152: 547–554, 1998.
45.
SwanwickGR, KirbyM, BruceI, BuggyF, CoenRF, CoakleyD, LawlorBA. Hypothalamic-pituitary-adrenal axis dysfunction in Alzheimer's disease: Lack of association between longitudinal and cross-sectional findings. Am J Psychiatry155: 286–289, 1998.
46.
O'BrienJT, AmesD, SchweitzerI, ColmanP, DesmondP, TressB.Clinical and magnetic resonance imaging correlates of hypothalamic-pituitary-adrenal axis function in depression and Alzheimer's disease. Br J Psychiatry168: 679–687, 1996.
De KloetER, OitzlMS, SchobitzB.Cytokines and the brain corticosteroid receptor balance: Relevance to pathophysiology of neuroendocrine-immune communication. Psychoneuroendocrinology19: 121–134, 1994.
50.
TombaughGC, YangSH, SwansonRA, SapolskyRM. Glucocorticoids exacerbate hypoxic and hypoglycemic hippocampal injury in vitro: Biochemical correlates and a role for astrocytes. J Neurochem59: 137–146, 1992.
51.
O'BrienJT, AmesD, SchweitzerI, MastwykM, ColmanP.Enhanced adrenal sensitivity to adrenocorticotrophic hormone (ACTH) is evidence of HPA axis hyperactivity in Alzheimer's disease. Psychol Med26: 7–14, 1996.
52.
HatzingerM, Z'BrunA, HemmeterU, SeifritzE, BaumannF, Holsboer-TrachslerE, HeuserIJ. Hypothalamic-pituitary-adrenal system function in patients with Alzheimer's disease. Neurobiol Aging16: 205–209, 1995.
53.
van der MeerMJ, SweepCG, RijnkelsCE, PesmanGJ, TildersFJ, KloppenborgPW, HermusAR. Acute stimulation of the hypothalamic-pituitary-adrenal axis by IL-1β, TNF-α, and IL-6: A dose-response study. J Endocrinol Invest19: 175–182, 1996.
54.
TurnbullAV, LeeS, RivierC.Mechanisms of hypothalamic-pituitary-adrenal axis stimulation by immune signals in the adult rat. Ann N Y Acad Sci840: 434–443, 1998.
55.
TomimotoH, AkiguchiI, WakitaH, KinoshitaA, IkemotoA, NakamuraS, KimuraJ.Glial expression of cytokines in the brains of cerebrovascular diseased patients. Acta Neuropathol92: 281–287, 1996.
56.
RaberJ, SorgO, HornTF, YuN, KoobGF, CampbellIL, BloomFE. Inflammatory cytokines: Putative regulators of neuronal and neuroendocrine function. Brain Res Brain Res Rev26: 320–326, 1998.
57.
GruolDL, NelsonTE. Physiological and pathological roles of interleukin-6 in the central nervous system. Mol Neurobiol15: 307–339, 1997.
HullM, FiebichBL, LiebK, StraussS, BergerSS, VolkB, BauerJ.Interleukin-6-associated inflammatory processes in Alzheimer's disease: New therapeutic options. Neurobiol Aging17: 795–800, 1996.
60.
HullM, StraussS, BergerM, VolkB, BauerJ.The participation of interleukin-6, a stress-inducible cytokine, in the pathogenesis of Alzheimer's disease. Behav Brain Res78: 37–41, 1996.
61.
PapassotiropoulosA, BagliM, JessenF, BayerTA, MaierW, RaoML, HeunR.A genetic variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk for sporadic Alzheimer's disease. Ann Neurol45: 666–668, 1999.
62.
ErshlerWB, SunWH, BinkleyN.The role of interleukin-6 in certain age-related diseases. Drugs Aging5: 358–365, 1994.
63.
PapanicolaouDA, WilderRL, ManolagasSC, ChrousosGP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med128: 127–137, 1998.
64.
FagarasanMO, AisenPS. IL-1 and anti-inflammatory drugs modulate A β cytotoxicity in PC12 cells. Brain Res723: 231–234, 1996.
65.
Del BoR, AngerettiN, LuccaE, De SimoniMG, ForloniG.Reciprocal control of inflammatory cytokines, IL-1 and IL-6, and β-amyloid production in cultures. Neurosci Lett188: 70–74, 1995.
66.
FiebichBL, LiebK, HullM, BergerM, BauerJ.Effects of NSAIDs on IL-1β-induced IL-6 mRNA and protein synthesis in human astrocytoma cells. Neuroreport7: 1209–1213, 1996.
67.
RaberJ, O'SheaRD, BloomFE, CampbellIL. Modulation of hypothalamic-pituitary-adrenal function by transgenic expression of interleukin-6 in the CNS of mice. J Neurosci17: 9473–9480, 1997.
68.
HeyserCJ, MasliahE, SamimiA, CampbellIL, GoldLH. Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin-6 in the brain. Proc Natl Acad Sci U S A94: 1500–1505, 1997.
69.
CampbellIL. Transgenic mice and cytokine actions in the brain: Bridging the gap between structural and functional neuropathology. Brain Res Brain Res Rev26: 327–336, 1998.
Di SantoE, AlonziT, FattoriE, PoliV, CilibertoG, SironiM, GnocchiP, Ricciardi-CastagnoliP, GhezziP.Overexpression of interleukin-6 in the central nervous system of transgenic mice increases central but not systemic proinflammatory cytokine production. Brain Res740: 239–244, 1996.
72.
BrettFM, MizisinAP, PowellHC, CampbellIL. Evolution of neuropathologic abnormalities associated with blood-brain-barrier breakdown in transgenic mice expressing interleukin-6 in astrocytes. J Neuropathol Exp Neurol54: 766–775, 1995.
73.
DammannO., LevitonA.Maternal intrauterine infection, cytokines, and brain damage in the pre-term newborn. Pediatr Res42: 1–8, 1997.
74.
MattilaKM, PirtillaT, BlennowK, WallinA, ViitanenM, FreyH.Altered blood-brain-barrier function in Alzheimer's disease?Acta Neurol Scand89: 192–198, 1994.
75.
HampelH, KotterHU, MollerHJ. Blood-cerebrospinal fluid barrier dysfunction for high molecular weight proteins in Alzheimer disease and major depression: Indication for disease subsets. Alzheimer Dis Assoc Disord11: 78–87, 1997.
76.
WolfM, BohmS, BrandM, KreymannG.Proinflammatory cytokines interleukin-1β and tumor necrosis factor-α inhibit growth hormone stimulation of insulin-like growth factor-1 synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. Eur J Endocrinol135: 729–737, 1996.
77.
FanJ, WojnarMM, TheodorakisM, LangCH. Regulation of insulin-like growth factor (IGF)-1 mRNA and peptide and IGF-binding proteins by interleukin-1. Am J Physiol270: R621–R629, 1996.
78.
LeePD, GiudiceLC, ConoverCA, PowellDR. Insulin-like growth factor protein-1: Recent findings and new directions. Proc Soc Exp Biol Med216: 319–357, 1997.
79.
De BenedettiF, AlonziT, MorettaA, LazzaroD, CostaP, PoliV, MartiniA, CilibertoG, FattoriE.Interleukin-6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-1: A model for stunted growth in children with chronic inflammation. J Clin Invest99: 643–650, 1997.
80.
FanJ, LiYH, BagbyGJ, LangCH. Modulation of inflammation-induced changes in insulin-like growth factor (IGF)-1 and IGF binding protein-1 by anti-TNF antibody. Shock4: 21–26, 1995.
81.
KolS, Ben-ShlomoI, AndoM, AdashiEY. Inuslin-like growth factor-1 affects the intraovarian interleukin-1 system: Evidence for suppression of type I interleukin-1 receptor expression and enhancement of secretory phospholipase A2 expression and activity. Mol Hum Reprod3: 1095–1099, 1997.
82.
YakarS, LiuJL, StannardB, ButlerA, AcciliD, SauerB, LeRoithD.Normal growth and development in the absence of hepatic insulin-like growth factor-1. Proc Natl Acad Sci U S A96: 7324–7329, 1999.
83.
ThissenJP, VerniersJ.Inhibition by interleukin-1β and tumor necrosis factor-α of the insulin-like growth factor-1 messenger ribonucleic acid response to growth hormone in rat hepatocyte primary culture. Endocrinology138: 1078–1084, 1997.
84.
FerryRJJr.., CerriRW, CohenP.Insulin-like growth factor binding proteins: New proteins, new functions. Horm Res51: 53–67, 1999.
85.
DeyBR, SpenceSL, NissleyP, FurlanettoRW. Interaction of suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor receptor. J Biol Chem273: 24095–24101, 1998.
86.
KullichW, KleinG.Possible effect of hormones on immune and inflammatory processes in female patients with chronic polyarthritis. Acta Med Austriaca23: 119–123, 1996.
87.
van de LooFA, AmtzOJ, van EnckevortFH, van LentPL, van den BergWB. Reduced cartilage proteoglycan loss during zymosan-induced gonarthritis in NOS2-deficient mice and in anti-interleukin-1-treated wild-type mice with unabated joint inflammation. Arthritis Rheum41: 634–646, 1998.
88.
KörnerH, RimingtonDS, StricklandDH, LemckertFA, PollardJD, SedgwickJD. Critical points of tumor necrosis factor action in central nervous system autoimmune inflammation defined by gene targeting. J Exp Med186: 1585–1590, 1997.
89.
YatemanME, ClaffeyDC, Cwyfan HughesSC, FrostVJ, WassJA, HollyJM. Cytokines modulate the sensitivity of human fibroblasts to stimulation with insulin-like growth factor-1 (IGF-1) by altering endogenous IGF-binding protein production. J Endocrinol137: 151–159, 1993.
90.
RozenF, ZhangJ, PollakM.Antiproliferative action of tumor necrosis factor-α on MCF-7 breast cancer cells is associated with increased insulin-like growth factor binding protein-3 accumulation. Int J Oncol13: 865–869, 1998.
91.
FanJ, CharD, BagbyGJ, GelatoMC, LangCH. Regulation of insulin-like growth factor-1 (IGF-1) and IGF-binding proteins by tumor necrosis factor. Am J Physiol269: R1204–R1212, 1995.
92.
VentersHD, TangQ, LiuQ, VanHoyRW, DantzerR, KelleyKW. A new mechanism of neurodegeneration: A proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc Natl Acad Sci U S A96: 9879–9884, 1999.
93.
OkuboY, BlakesleyVA, StannardB, GutkindS, LeRoithD.Insulin-like growth factor-1 inhibits the stress-activated protein Kinase/c-jun N-terminal kinase. J Biol Chem273: 25961–25966, 1998.
SortinoMA, CanonicoPL. Neuroprotective effect of insulin-like growth factor-1 in immortalized hypothalamic cells. Endocrinology137: 1418–1422, 1996.
96.
BruunsgaardH, Andersen-RanbergK, JeuneB, PedersenAN, SkinhojP, PedersenBK. A high plasma concentration of TNF-α is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci54: M357–M364, 1999.
97.
PaolissoG, AmmendolaS, Del BuonoA, GambardellaA, RiondinoM, TagliamonteMR, RizzoMR, CarellaC, VarricchioM.Serum levels of insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive function. J Clin Endocrinol Metab82: 2204–2209, 1997.
98.
MustafaA, LannfeltL, LiliusL, IslamA, WinbladB, AdemA.Decreased plasma insulin-like growth factor-1 level in familial Alzheimer's disease patients carrying the Swedish APP 670/671 mutation. Dement Geriatr Cogn Disord10: 446–451, 1999.
99.
BeccariaL, MarzianiE, ManzoniP, ArvatE, ValettoMR, GianottiL, GhigoE, ChiumelloG.Further evidence of cholinergic impairment of the neuroendocrine control of the GH secretion in Down's syndrome. Dement Geriatr Cogn Disord9: 78–81, 1998.
HestnesA, StovnerLJ, HusoyO, FoilingI, SjaastadO.Somatomedin C (insulin-like growth factor-1) in adults with Down's syndrome. J Ment Defic Res35: 204–208, 1991.
102.
AnnerenG, GustavsonKH, SaraVR, TuvemoT.Growth retardation in Down's syndrome in relation to insulin-like growth factors and growth hormone. Am J Med Genet7(Suppl): 59–62, 1990.
103.
AnnerenG, SaraVR, HallK, TuvemoT.Growth and somatomedin responses to growth hormone in Down's syndrome. Arch Dis Child61: 48–52, 1986.
104.
CentoRM, RagusaL, ProtoC, AlbertiA, FioreG, SorannaL, ColabucciF, LanzoneA.Growth hormone administration normalizes the ovarian responsiveness to follicle-stimulating-hormone in the early stages of the follicular maturation in women with Down's syndrome. J Endocrinol Invest21: 342–347, 1998.
105.
AnwarAJ, WalkerJD, FrierBM. Type 1 diabetes mellitus and Down's syndrome: Prevalence, management, and diabetic complications. Diabet Med15: 160–163, 1998.
SteinGR, JewellRC. Down's syndrome, hypothyroidism, and diabetes mellitus in an adult. Med J Aust2: 9–10, 1979.
108.
KalmanJ, JuhaszA, LairdG, DickensP, JardanhazyT, RimanoczyA, BonczI, Parry-JonesWL, JankaZ.Serum interleukin-6 levels correlate with the severity of dementia in Down's syndrome and in Alzheimer's disease. Acta Neurol Scand96: 236–240, 1997.
109.
MurphyM, FriendDS, Pike-NobileL, EpsteinLB. Tumor necrosis factor-α and IFN-γ expression in human thymus: Localization and overexpression in Down's syndrome (trisomy 21). J Immunol149: 2506–2512, 1992.
110.
MurphyM, HyunW, HunteB, LevineAD, EpsteinLB. A role for tumor necrosis factor-α and interferon-γ in the regulation of interleukin-4-induced human thymocyte proliferation in vitro: Heightened sensitivity in the Down's syndrome (trisomy 21) thymus. Pediatr Res32: 269–276, 1992.
111.
GriffinWS, StanleyLC, LingC, WhiteL, MacLeodV, PerrotLJ, WhiteCLIII, AraozC.Brain interleukin-1 and S-100 immunoreactivity are elevated in Down's syndrome and Alzheimer's disease. Proc Natl Acad Sci U S A86: 7611–7615, 1989.
