神经免疫内分泌调节环路
2011-11-24 16:46:31   来源：   作者：  评论：0 点击：

　　各种生物活性物质对神经、免疫、内分泌三大系统的作用不是独立进行的，整体条件下基本是以较完整的环路为单位，构成复杂的网络。这些环路的工作方式是正反馈和负反馈，有调节精确、放大效应、整合效应、自限性及级联反应等特点。以下例举几种典型的神经内分泌免疫调节环路。

　　（一）下丘脑-垂体前叶-肾上腺皮质与Mo-Mφ环路（HPA-Mo/Mφ）

　　此环路的中心成分为CRH-ACTH-GC-IL-1。具体环节如下：

　　（1）下丘脑的CRH促进垂体前叶释放ACTH，后者刺激GC大量分泌，引起血中GC浓度升高。（2）ACTH及GC可分别抑制Mo-Mφ的功能，减少IL-1的生成。

　　（3）受刺激后活化的Mo-Mφ生成IL-1增加，而IL-1则作用于下丘脑促进CRH释放，作用于垂体前叶诱导ACTH的分泌，也有报导IL-1直接刺激肾上腺皮质分泌GC。

　　（4）ACTH有GC限制IL-1的进一步生成，且ACTH前体POMC还可裂解释放α-MSH，而α-MSH可在中枢水平对抗IL-1对CRH分泌的刺激效应。见图10-5。

图10-5 HPA与Mo-Mφ轴系
注：+兴奋 -抑制

　　（二）下丘脑-垂体前叶-肾上腺皮质与胸膛环路

　　此环路有如下环节：

　　（1）HPA轴中ACTH和GC均可抑制胸腺的功能，包括细胞增殖及胸膛激素分泌。

　　（2）胸腺激素中thymosin α1及thymulin等都能刺激ACTH的分泌。

　　（3）胸腺中含CRH受体并可合成CRH，而CRH对胸腺的某些功能有刺激效应。见图10-6。

图10-6 HPA与胸腺轴系

　　（三）下丘脑-垂体前叶与胸腺环路

　　（1）下丘脑分泌GHRH、PRF和TRH，作用于垂体前叶，刺激GH和PRL的分泌。

　　（2）GH和PRL影响胸腺的发育、细胞的功能及激素的合成，胸腺中可合成GH、PRL。

　　（3）胸腺肽可刺激GH及PRL从垂体前叶释放。

　　（四）下丘脑-垂体前叶-性腺轴系与胸腺环路

　　（1）LHRH刺激垂体前叶释放LH/FSH，二者引起性腺分泌雄激素、雌激素及孕激素。

　　（2）这些类固醇激素对胸腺功能有较强的抑制性效应，如使胸腺体积减少、细胞数目减少、细胞免疫功能障碍等。

　　（3）胸腺肽中thymosin β4可在离体条件下刺激下丘脑释放LHRH。

　　（4）胸腺还可分泌一种蛋白成分，强有力地抑制性腺分泌性激素。

　　（5）LHRH也可由胸遥小皮细胞合成。

　　（6）卵巢中有thymosin原的存在。
图10-7 下丘脑-垂体前体与胸腺环路

图10-8 HPG与胸腺的联系

　　神经、免疫和内分泌系统间有经常性的信息往返交流，此种联系对各系统的生理功能是必不可少的。由于三大系统均共享各种生物活性物质，如GH和PRL既是神经内分泌激素，也可视为免疫因子，而IL-1或IL-2也可称做神经介质或神经派往素亦不为过。因此，众多信息分子的原有命名已不足以恰当概括其多重活性。免疫系统可感觉机体内环境的理化和生物性改变，同时还可能具备对感受的信息进行加工、处理、存贮及整合等功能，这引起特点与神经系统有一定的相似性。免疫功能的执行服从于整体需求，如在应激条件下，免疫系统活动减弱，以保证机体充分应付与生存悠关的体内外各种条件改变。再如妊娠时，保持胎盘的免疫抑制状态，有利于胚胎的顺利发育。已在众多疾病的病理及病理生理过程中，找到神经免疫内分泌交互作用的证据。相信随着研究的深入，必将提示更多疾病与神经免疫内分泌网络的联系，从而为临床的诊治提供新的思路、手段和药物。神经免疫内分泌学的研究也将有助于提示脑的奥秘。
（张万会）

参考文献

　　1.Aird F,et al.Corticotropin-releasing factor mRNA in rat thymus and spleen.Proc Natl Acad Sci USA,1993;90:7104

　　2.Amano Y,et al.Inhibition by glucocorticoids of the formation of interliukinlα，interleukinlβ and interleukin-6:mediation by decreased mRNa stability.Mol Pharmacol,1993;43:176

　　3.Araujo DM.et al.Trophic effects of interleukin-4,7 and 8 on hippocampla cultures:potential involvement of glia-derived factor.Brain Res,1993;600:49

　　4.Ban EM,et al.Identification of suppressin-producing cells in the rat pituitary.Endocrinology,1993;133:241

　　5.Berkenbosch F,et al.CRF-producing neurons in the rat activated by interleukin-1.Science,1987;238:524

　　6.Bernadini R,et al.Rat hypothalamic CRH secretion in vitro is stimulated by IL-1 in an eicosanoid-dependent manner.Life Sci,1990;47:1601

　　7.Berczi I.Pituitary function and Immunity.CRC Press Inc.Boca Raton Florida.1986

　　8.Buzzetti R,et al.A critical assessment of the interactions between the immune system and the hypothalamus-pituitary-adrenalaxis.j Endocrinol,1989;120:183

　　9.Celada A,et al.Repression of major histocompatibility complex I-a expression by glucocorticoids:the glucocorticoid receptor inhibits the DNa binding of the X box DNA binding protein.J Exp Med ,1993;177:691

　　10.Chao CC,et al.Activated microglia mediate nediate neuronal cell injury via a nitric oxide mechanism.J Immunol,1992;149:2736

　　11.Christ M,et al.The inositol-1,4,5-trisphosphate system is involved in repid effects of aldosterone in human mononuclear leukocytes.J cLIN eNDOCRINOl mETAB,193;77:1452

　　12.Cirino G,et al.Anti-inflammatory action of an N-terminal peptide from human lipocortin-1,Brit J Pharmacol,1990;104:573

　　13.DuBois CM,et al.Hematopoietic growth factors and hlucocorticoids synergize to mimic the effects of IL-1 on granulocyte differentiation and IL-1 receptor induction on bone marrow cells in vi.Exp Hematol,1993;21:303

　　14.Effros RB,et al.Influence of age and caloric restriction on macrophage IL-6 and TNF production.Lymphok Cytok Res,1991;10:347

　　15.Flecher-Chiappini SE,et al.Glucocorticoid-prolactin interactions in Nb2lymphoma cells:antiproliferative versus anticytolytic effects.Proc Soc Exp Biol Med,1993;202:345

　　16.Freidin M and Kessler JA.Cytokine regulation of substance Pexpression in sympathetic neurons. Proc Natl Acad Sci UCA,1991;88:3200

　　17.Garcia I,et al.β-Endorphin inhibits IL-2 release and expression of IL-2receptors in Con A-stimulated splenic lymphocytes.Lymphok Cytok Res,1992;11:339

　　18.Guilian D and Lachman L.Interleukin 1 stimulation of astroglial proliferation after grain injury.Science,1984;228:497

　　19.Haines KA,et al.Chemoattraction of neurtrophils by substance P and transforming growth factor β1 is inadequately explained by current models of lipid remodelling.J Immunol,1993;151:1491

　　20.Hart RP,et al.Substance P gene expression is regulated by interleukin-1 in cultured sympathetic ganglia.J Neurosci Res ,1991;29:282

　　21.Heagy W,et al.Opioid receptor agonists and Ca2+modulation by interleukin-1 in cultured sympathetic ganglia.J Neurosci Res,1991;29:282

　　22.Hiramoto R,et al.Identification of specific pathways of communication between the CNS and NK cell system.Life Sci,1993;53:527

　　23.Jonakati GM.Neural immune interations in sympathetic ganglia.TINS,1993;16:419

　　24.Katsuura G,et al.Interleukin-1 beta increases prostaglanken E2 in rat astrocyte cultrues:modulatory effect of neuropeptides.Endocrinology,1989;124:3125

　　25.Kim KS,et al.Modulation of bloodbrain barrier permeability by tumor necrosis facto and antibody to tumor necrosis factor in the rat.Lymphok Cytok rES,1992;11:293

　　26.kIMAALL ES,et al. Substance P,neurokinin A,and neurokinin Binduce generation of IL-1 like activity in P388D1 cells.j Immunol,1988;141:356427.

　　27.Koike K,et al.Tumor necrosis factor-alpha increases release of arachidonate and prolactin from rat anterior pituitary cells.Endocrinology,1991;128:2791

　　28.Kraiem A,et al.Effects of gamma-interferon on Dr antigen expression,growth,3.5.3'-triidothyronine secretion ,iodide uptake and cyclic adenosine monophosphate accumulation in cultured human thyroid cells.j Clin Endocrin Metab,1990;71:817

　　29.Kroemer G,et al.Physiology and pathology of an immunoendocrine feedback loop.Immunol Today,1988;9:163

　　30.Lee SC,et al.Macrophage-colony-stimulating factor in human fetal astrocytes and microglia.Differential regulation by cytokines and lipopolysaccharide,and modulation of class II MHC on microglia.j Immunol,1993;150:594

　　31.Louis J-C,et al. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death.Science,1993;259:689

　　32.Low KG,et al.Differential regulation of proenkephalin expression in astrocytes by cytokines.Endocrinology,1992;131:1908

　　33.Lyson K,et al.Involvement of arachidonic acid cascade in IL-6 stimulated CRF release in vitro.Neuroendocrinol,1992;55:708

　　34.McGeer PL,et al.Reactive microglia are positive for HLA-Dr in the substantia nigra of Parkinson's and Alzheimer's disease brains.Neurology,1988;38:1285

　　35.Milenkovic L,et al.Cachectin alters anterior pituitary hormone release by a direct action in vitro.Proc Natl　Acad　Sci USA,1989;86:2418

　　36.Millington G and Buckingham JC,Thymic peptides and neuroendocrine immunecommunication.J Endocrinol.1992;133:163

　　37.Muller H,et al.Interfaeron alpha 2-induced stimulation of ACTH and cortisol secretion in man.Neuroendocrinol,1991;54:499

　　38.Naiboh Y,et al.Interleukin-6 stimulates the secretion of corticotropin in conscious freely moving rats.BBRC,1988;155:1459　

　　39.Nistico G.Communications among ceutral nervous system,neuroendocrine and immune systems:interleukin 2.Progr Neurodiol,1993;10:463

　　40.Nohava K,et al.Neurons and neuroblastoma as source of macrophage colony stimulating factor.Eur J Immunol.

　　41.Patterson PH and Nawa H.Neuronal differentiation factors/cytokines and synaptic piasticity.Neuron 10(suppl)1993;10(suppl):123

　　42.Perry VH,et al.Macrophages and inflammation in the central nervous system.TINS,1993;16:268

　　43.Rabin BS,et al.Bidirectional interaction between the central nervous system and the immune system.Critical Rev Immunol,1989;9:279.

　　44.Rogister B,et al.Transforming growth factor beta as a neuroglial signal during peripheral nervous system response to injury.J.Neurosci Res,1993;34:32

　　45.Selmaj KW,et al.Proliferation of astrocytes in vitro in response to cytokines.A primary role for tumor necrosis factor.J Immunol,1990;144:129

　　46.Shieh　JH,et al.Cytokines and dexamethasone modulation of IL-1receptors on human neutrophils in vitro.J Immunol.1993;150:3515

　　47.Spangelo BL,et al.Induction of interlukin-6 release by interleukin-1 in rat anterior pituitary cells in vitro:Evidence for an eicosanoid dependent mehanism.Endocrinology,1991;129:2886

　　48.Spinedi E,et al.Cytokine stimulates the CRH but not the vasopressin neuronal system:evidence for a median eminence site of interleukin-6action.Neuroendocrinol.1992;56:46

　　49.Tsagarakis S,et al.Interleukin-1 directly stimulates the release of corticotropin releasing factor from rat hypothalamus,Neuroendocrinol,1989;49:98

　　50.Tsitsiloni OE,et al.Expression of α-thymosins in human tissues in normal and abnormal growth.Proc Natl Acad Sci USA.1993;90:9504

　　51.Vankelecom H,et al.Evidence that folliculostillate cells mediate the inhibitory effect of interferon-γ on hormone secretion in rat anterior pituitary cell cultures .Endocrinology,1992;130:3537

　　52.Yamashita H,et al.Effects of intekleukin 1β on membrane potentials of hypothalamic meurons in rats in vitro.Amm NY Acad Sci,1993;689:689

　　53.徐仁宝.躯体性和心理性应激.复量神经生物学讲座.1991；7：85