Download PDF
Am J Perinatol 2000; 17(8): 393-404
DOI: 10.1055/s-2000-13457
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

CYTOKINES AND NEONATES

Mirjana Nesin, Susana Cunningham-Rundles
  • Department of Pediatrics, Division of Neonatology, Weill Medical College of Cornell University, New York, New York
Further Information

Publication History

Publication Date:
31 December 2000 (online)

Also available at
    Permissions and Reprints

ABSTRACT

This review is a short synopsis of the roles cytokines play during fetal life, initiation of labor, and in neonatal immunity and diseases. Hematopoietic growth factors regulate the maturation of progenitors in fetal and neonatal hematopoietic organs. Cytokines act as extra-hematopoietic growth factors, modulators of feto-maternal tolerance and are involved in selective apoptosis during tissue remodeling. Inter-regulation of cytokine networks is critical for normal function and maturation of neonatal host defenses. Antigen specific immunity develops later in life and neonates initially depend on natural (innate) immunity. Cytokines regulate innate immunity and connect it with antigen specific adaptive immunity. Some cytokines have already found a place in routine NICU therapy (EPO and G-CSF), while diagnostic and therapeutic uses of others are under investigation (TPO, TNF-α, etc.).

KEYWORD

Cytokines - pro-inflammatory cytokines - neonatal sepsis - premature labor - NEC - PVL - developmental immunology

REFERENCES

  • 1 Wilson M, Seymour R, Henderson B. Bacterial pertubation of cytokine networks.  Infect Immun . 1998;  66 2401-2409
    PubMedGoogle Scholar
  • 2 Metinko A P. Neonatal pulmonary host defense mechanisms. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology 2nd ed. Philadelphia: WB Saunders 1998: 2047-2062
    Google Scholar
  • 3 Slayton W. Development of the immune system in the fetus. In: Christensen RD, ed. Hematologic Problems of the Neonate Philadelphia: WB Saunders 2000: 21-41
    Google Scholar
  • 4 Schibler K R. Developmental biology of hematopoietic growth factors. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology 2nd ed. Philadelphia: WB Saunders 1998: 1737-1753
    Google Scholar
  • 5 Hume D A, Perry V H, Gordon S. Immunohistochemical localization of macrophage-specific antigen in developing mouse embryos: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers.  J Cell Biol . 1983;  97 253-257
    CrossrefPubMedGoogle Scholar
  • 6 Stallmach T, Hebisch G, Joller-Jemelka H I. Cytokine production and visualized effects in the feto-maternal unit: quantitative and topographic data on cytokines during intrauterine disease.  Lab Invest . 1995;  73 384-392
    PubMedGoogle Scholar
  • 7 Bennett W A, Lagoo-Deenadayalan S, Brackin M N. Cytokine expression by models of human trophoblast as assessed by rt-PCR.  Am J Reprod Immunol . 1996;  36 285-294
    PubMedGoogle Scholar
  • 8 Malahotra I, Ouma J, Wamachi A. In utero exposure to helminth and mycobacterial antigens generates cytokine responses similar to that observed in adults.  J Clin Invest . 1997;  99 1759-1766
    PubMedGoogle Scholar
  • 9 Lin H, Mosmann T R, Guilbert L. Synthesis of T helper 2 type cytokines at the maternal-fetal interface.  J Immuniol . 1993;  151 4562-4573
    PubMedGoogle Scholar
  • 10 Juul S E. Nonhematopoietic actions of hematopoietic growth factors in the fetus and neonate. In: Christensen RD, ed. Hematologic Problems of the Neonate Philadelphia: WB Saunders 2000: 61-78
    Google Scholar
  • 11 Juul S E, Anderson D K, Li Y, Christensen R D. Erythropoietin and erythropoietin receptor in the developing human.  CNS Pediatr Res . 1998;  43 40-49
    PubMedGoogle Scholar
  • 12 Maysinger D, Berezovskaya O, Fedoroff S. CSF-1 is also a growth factor in CNS.  Exp Neurol . 1996;  141 47-56
    CrossrefPubMedGoogle Scholar
  • 13 Marti H H, Wenger R H, Rivas L A. Erythropoietin gene expression in human, monkey and murine brain.  Eur J Neurosci . 1996;  8 666-676
    PubMedGoogle Scholar
  • 14 Yamaji R, Okada T, Moriya M. Brain capillary endothelial cells express two forms of erythropoietin receptor mRNA.  Eur J Biochem . 1996;  239 494-500
    CrossrefPubMedGoogle Scholar
  • 15 Morishita E, Masuda S, Nagao M. erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death.  Neuroscience . 1997;  76 105-116
    PubMedGoogle Scholar
  • 16 Tweardy D J, Glazer E W, Mott P L, Anderson K. Modulation by TNF-alpha of human astroglial cell production of GM-CSF and G-CSF.  J Neuroimmunol . 1991;  32 269-278
    CrossrefPubMedGoogle Scholar
  • 17 Takao T, Tojo C, Nishioka T. Corticotropin-releasing factor treatment upregulates IL-1 receptors in the mouse pituitary: reversal by dexamethasone.  Brain Res . 1995;  688 219-222
    CrossrefPubMedGoogle Scholar
  • 18 Opsjon S L, Wathen N C, Tingulstad S. TNF-α, IL-1, and IL-6 in normal human pregnancy.  Am J Obstet Gynecol . 1993;  169 397-404
    PubMedGoogle Scholar
  • 19 Romero R, Gomez R, Ghezzi F. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition.  Am J Obstet Gynecol . 1998;  179 186-193
    CrossrefPubMedGoogle Scholar
  • 20 Steinborn A, Kuhnert M, Halberstadt E. Immunomodulating cytokines induce term and preterm partuition.  J Perinatal Med . 1996;  24 381-390
    PubMedGoogle Scholar
  • 21 Romero R, Brody D T, Oyarzun E. Infection and labor: III. IL-1 a signal for the onset of parturition.  Am J Obstet Gynecol . 1989;  160 1117-1123
    PubMedGoogle Scholar
  • 22 Romero R, Gomez R, Ghezzi F. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition.  Am J Obstet Gynecol . 1998;  179 186-193
    CrossrefPubMedGoogle Scholar
  • 23 Hirsch E, Blanchard R, Mehta S P. Differential fetal and maternal contributions to the cytokine milieu in a murine model of infection-induced preterm birth.  Am J Obstet Gynecol . 1999;  180 429-434
    PubMedGoogle Scholar
  • 24 Steinborn A, Niederhut A, Solbach C, Hildenbrand R, Sohn C, Kaufmann M. Cytokine release from placental entothelial cells: a process associated with preterm labor in the absence of intrauterine infection.  Cytokine . 1999;  11 66-73
    CrossrefPubMedGoogle Scholar
  • 25 Teti G, Mancuso G, Tomasello F. Cytokine appearance and effects of anti-TNF alpha antibodies in a neonatal rat model of group B streptococcal infection.  Infection and Immunity . 1993;  61 227-235
    PubMedGoogle Scholar
  • 26 Berner R, Niemeyer C M, Leititis J U. Plasma levels and gene expression of G-CSF, TNF-alpha, IL-1, IL-6, IL-8 and soluble intercelullar adhesion molecules in neonatal early onset sepsis.  Pediatr Res . 1998;  44 469-477
    CrossrefPubMedGoogle Scholar
  • 27 Eckmann L, Kagnoff M F, Fierer J. Epithelial cells secrete the chemokine IL-8 in response to bacterial entry.  Trends Microbiol . 1995;  3 118-120
    CrossrefPubMedGoogle Scholar
  • 28 Wolbink G J, Bossink A W, Groneweld A B. Complement activation in patients with sepsis is in part mediated by C-Reactive protein.  J Infect Dis . 1998;  177 81-87
    PubMedGoogle Scholar
  • 29 Slayton W. Development of the immune system in the fetus. In: Christensen RD. Hematologic Problems of the Neonate Philadelphia: WB Saunders 2000: 21-41
    Google Scholar
  • 30 Kilpatrick L, Harris M C. Cytokine and the inflammatory response. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology, 2nd ed. Philadelphia: WB Saunders 1998: 1967-1980
    Google Scholar
  • 31 Lewis D B. Host defense mechanisms against bacteria, fungi, viruses and nonviral intracellular pathogens. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology 2nd ed. Philadelphia: WB Saunders 1998: 1869-1919
    Google Scholar
  • 32 Abbas A K, Lichtman A H, Pober J S. Cellular and Molecular Immunology.  3rd ed. Philadelphia: WB Saunders 1997: 250-277
    Google Scholar
  • 33 Bouvet J P, Fischetti V A. Diversity of antibody-mediated immunity at the mucosal barrier.  Infect Immunit . 1999;  67 2687-2691
    PubMedGoogle Scholar
  • 34 Takahashi I, Kiyono H. Gut is the largest immunologic tissue.  JPEN . 1999;  23 S7-S12
    PubMedGoogle Scholar
  • 35 Casadevall A, Pirofski L A. Host-pathogen interactions: redefining the basic concepts of virulence and pathogenicity.  Infect Immunit . 1999;  67 3703-3713
    PubMedGoogle Scholar
  • 36 Buescher E S, Malinowska I. Soluble receptors and cytokine antagonists in human milk.  Pediatr Res . 1996;  40 839-844
    PubMedGoogle Scholar
  • 37 Grether J K, Nelson K B. Maternal infection and cerebral palsy in infants of normal birth weight.  JAMA . 1997;  278 207-210
    CrossrefPubMedGoogle Scholar
  • 38 Leviton A, Paneth N, Reuss M L. Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants.  Ped Res . 1999;  46 566-575
    CrossrefPubMedGoogle Scholar
  • 39 Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn.  Ped Res . 1997;  42 1-8
    CrossrefPubMedGoogle Scholar
  • 40 Cai Z, Pan Z L, Pang Y, Evans O B, Rhodes P G. Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal LPS administration.  Ped Res . 2000;  47 64-72
    PubMedGoogle Scholar
  • 41 Balasingam V, Tejada-Berges T, Wright E, Bouckova R, Yong V W. Reactive astrogliosis in the neonatal mouse brain and its modulation by cytokines.  J Neurosci . 1994;  14 846-856
    PubMedGoogle Scholar
  • 42 Gilles F H, Leviton A, Kerr C S. Endotoxin leukoencephalopathy in the telencephalon of the newborn kitten.  J Neurol Sci . 1976;  27 183-191
    CrossrefPubMedGoogle Scholar
  • 43 Quagliarello V J, Wispelwey B, Long W J, Scheld W M. Recombinant human IL-1 induces meningitis and blood-brain barrier injury in the rat: characterization and comparison with TNF-alpha.  J Clin Invest . 1991;  87 1360-1366
    PubMedGoogle Scholar
  • 44 Chao C C, Hu S, Close K. Cytokine release from microglia: differential inhibition by pentoxifylline and dexamethasone.  J Infect Dis . 1992;  166 847-853
    PubMedGoogle Scholar
  • 45 Fellman V, Raivio K O. Reperfusion injury as the mechanism of brain damage after perinatal asphyxia.  Ped Res . 1997;  41 599-606
    PubMedGoogle Scholar
  • 46 Rothwell N J, Hopkins S J. Cytokines and nervous system.  Trends Neurol Sci . 1995;  18 130-136
    CrossrefPubMedGoogle Scholar
  • 47 Vannucci R C. Experimental biology of cerebral hypoxia-ischemia: relation to perinatal brain damage.  Pediatr Res . 1990;  27 317-326
    PubMedGoogle Scholar
  • 48 Palmer C. Hypoxic-ischemic encephalopathy: therapeutic approaches against microvascular injury, and role of neutrophils PAF and free radicals.  Clin Perinatol . 1995;  22 481-517
    PubMedGoogle Scholar
  • 49 Etzioni A. Adhesion molecules: their role in health and disease.  Ped Res . 1996;  39 191-198
    PubMedGoogle Scholar
  • 50 Bry K, Lappalainen U, Hallman M. Intraamniotic IL-1 accelerates surfactant protein synthesis in fetal rabbits and improve lung stability after premature birth.  J Clin Invest. . 1997;  99 2992-2999
    CrossrefPubMedGoogle Scholar
  • 51 Dranoff G, Crawford A D, Sadelain M. Involvement of GM-CSF in pulmonary homeostasis.  Science . 1994;  264 713-716
    CrossrefPubMedGoogle Scholar
  • 52 Jobe A J. The new BPD: an arrest of lung development.  Ped Res . 1999;  46 641-643
    PubMedGoogle Scholar
  • 53 Miyazaki Y, Araki K, Vesin C. Expression of TNF-alpha transgene in murine lungs causes lymphocytic and fibrosing alveolitis.  J Clin Invest . 1995;  96 250-259
    PubMedGoogle Scholar
  • 54 Neu J, Weiss M D. Necrotizing enterocolitis: pathophysiology and prevention.  JPEN . 1999;  23 S13-S17
    CrossrefPubMedGoogle Scholar
  • 55 Pang K Y, Bresson J L, Walker W A. Development of gastrointestinal mucosal barrier: in utero maturation of the microvillus surface by cortisone.  Am J Physiol . 1985;  249 85-91
    PubMedGoogle Scholar
  • 56 Rotschild T, Nandgaonkar B N, Yu K, Higgins R D. Dexamethasone reduces oxygen induced retinopathy in a mouse model.  Ped Res . 1999;  46 94-99
    CrossrefPubMedGoogle Scholar
  • 57 Shannon K M, Keith J F, Mentzer W C. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants.  Pediatrics . 1995;  95 1-8
    PubMedGoogle Scholar
  • 58 Carr R, Modi N, Dore C J, El-Rifai R, Lindo D. A randomized controlled trial of prophylactic GM-CSF in human newborns less than 32 weeks' gestation.  Pediatrics . 1999;  103 796-802
    CrossrefPubMedGoogle Scholar
  • 59 Schibler K R, Osborne K A, Leung L Y, Le T V, Baker S I, Thompson D D. A randomized placebo-controlled trial of G-CSF administration to newborn infants with neutropenia and clinical signs of early-onset sepsis.  Pediatrics . 1998;  102 6-13
    CrossrefPubMedGoogle Scholar
  • 60 Du S, Lin Q, Williams D A. Protective effects of IL-11 in murine model of ischemic bowel necrosis.  Am J Physiol . 1997;  272 G545-G552
    PubMedGoogle Scholar
  • 61 Messer J, Eyer D, Donato L, Gallati H, Matis J, Simeoni U. Evaluation of IL-6 and TNF-alpha for early diagnosis of neonatal infection.  J Pediatr . 1996;  129 574-580
    CrossrefPubMedGoogle Scholar