Proinflammatory Cytokine-Receptor Interaction Model Improves the Predictability of Cerebral White Matter Injury in Preterm Infants

ABSTRACT

Proinflammatory cytokines have been variably linked to development of cerebral white matter injury (WMI) in preterm infants. Because soluble receptors tightly control cytokine bioactivity, we modeled cytokine-receptor interaction as a predictor of WMI. Plasma from 100 preterm infants was assayed for cytokines (tumor necrosis factor alpha, interleukin (IL-1β, IL-6) and their soluble receptors (sTNF-RI), sTNF-RII, sIL-1RA, and sIL-6R). Cranial ultrasound (US) results were correlated with cytokine and receptor concentrations individually and with cytokine-receptor interaction models (PROC LOGISTIC; SAS Software). Receiver operating characteristic curves were constructed to determine the predictability of WMI. Fifty-two infants with normal US exams were compared with 21 infants with evidence of WMI. There was no association between individual cytokine or receptor concentrations and the development of WMI. However, modeling cytokines with their soluble receptors significantly improved the predictability of WMI. We concluded that consideration of cytokine-receptor interaction may be more important than individual cytokine concentrations alone in determining the role of inflammation in the pathogenesis of WMI in preterm infants.

Tumor necrosis factor - interleukin-1β - interleukin-6 - soluble cytokine receptors - periventricular leukomalacia - periventricular hemorrhagic infarction

REFERENCES

• 1 Horbar J D, Badger G J, Carpenter J H et al.. Trends in mortality and morbidity for very low birth weight infants, 1991-1999.  Pediatrics. 2002;  110 143-151
• 2 Marlow N, Wolke D, Bracewell M A, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth.  N Engl J Med. 2005;  352 9-19
• 3 Taylor H G, Klein N, Minich N M, Hack M. Middle-school-age outcomes in children with very low birthweight.  Child Dev. 2000;  71 1495-1511
• 4 Whitaker A H, Feldman J F, Van Rossem R et al.. Neonatal cranial ultrasound abnormalities in low birthweight infants: relation to cognitive outcomes at six years of age.  Pediatrics. 1996;  98 719-729
• 5 Leijser L M, de Vries L S, Cowan F M. Using cerebral ultrasound effectively in the newborn infant.  Early Hum Dev. 2006;  82 827-835
• 6 Wu Y W, Colford Jr J M. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis.  JAMA. 2000;  284 1417-1424
• 7 Dammann O, Leviton A. Inflammatory brain damage in preterm newborns-dry numbers, wet lab, and causal inferences.  Early Hum Dev. 2004;  79 1-15
• 8 Yoon B H, Jun J K, Romero R et al.. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy.  Am J Obstet Gynecol. 1997;  177 19-26
• 9 Yoon B H, Romero R, Yang S H et al.. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia.  Am J Obstet Gynecol. 1996;  174 1433-1440
• 10 Ellison V J, Mocatta T J, Winterbourn C C, Darlow B A, Volpe J J, Inder T E. The relationship of CSF and plasma cytokine levels to cerebral white matter injury in the premature newborn.  Pediatr Res. 2005;  57 282-286
• 11 Bartha A I, Foster-Barber A, Miller S P et al.. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome.  Pediatr Res. 2004;  56 960-966
• 12 Nelson K B, Grether J K, Dambrosia J M et al.. Neonatal cytokines and cerebral palsy in very preterm infants.  Pediatr Res. 2003;  53 600-607
• 13 Kaukola T, Herva R, Perhomaa M et al.. Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm extremely low birth weight infants.  Pediatr Res. 2006;  59 478-483
• 14 Carter A, Haddad N, Draxler I, Tatarsky I. Effects of soluble interleukin-1 receptor and tumor-necrosis factor receptor, respectively, on the IL-1- and the TNF-alpha-induced DNA synthesis of acute myeloblastic leukemia blasts in vitro.  Eur J Haematol. 1994;  53 38-45
• 15 Kishimoto T, Akira S, Taga T. Interleukin-6 and its receptor: a paradigm for cytokines.  Science. 1992;  258 593-597
• 16 Taga T, Hibi M, Hirata Y et al.. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130.  Cell. 1989;  58 573-581
• 17 Goldenberg R L, Hauth J C, Andrews W W. Intrauterine infection and preterm delivery.  N Engl J Med. 2000;  342 1500-1507
• 18 Scheurich P, Uecer U, Kroenke M, Pfizenmaier K. Quantification and characterization of high affinity membrane receptors for tumor necrosis factor on human leukemic cell lines.  Int J Cancer. 1986;  38 127-133
• 19 Volpe J J. Neurology of the Newborn. 4th ed. Philadelphia; WB Saunders 2001
• 20 Levene M I. Measurement of the growth of the lateral ventricle in preterm infants with real-time ultrasound.  Arch Dis Child. 1981;  56 900-904
• 21 Hagberg H, Mallard C, Jacobsson B. Role of cytokines in preterm labour and brain injury.  BJOG. 2005;  112 16-18
• 22 Back S A, Riddle A, McClure M M. Maturation-dependent vulnerability of perinatal white matter in premature birth.  Stroke. 2007;  38 724-730
• 23 Sherwin C, Fern R. Acute lipopolysaccharide-mediated injury in neonatal white matter glia: role of TNF-alpha, IL-1beta, and calcium.  J Immunol. 2005;  175 155-161
• 24 Folkerth R D. Neuropathologic substrate of cerebral palsy.  J Child Neurol. 2005;  20 940-949
• 25 Nelson K B, Dambrosia J M, Grether J K, Phillips T M. Neonatal cytokines and coagulation factors in children with cerebral palsy.  Ann Neurol. 1998;  44 665-675
• 26 Yang G Y, Mao Y, Zhou L F et al.. Attenuation of temporary focal cerebral ischemic injury in the mouse following transfection with interleukin-1 receptor antagonist.  Brain Res Mol Brain Res. 1999;  72 129-137
• 27 Jonsson B, Tullus K, Brauner A, Lu Y, Noack G. Early increase of TNFα and IL-6 in tracheobronchial aspirate fluid indicator of subsequent chronic lung disease in preterm infants.  Arch Dis Child Fetal Neonatal Ed. 1997;  77 F198-F201
• 28 Buck C, Bundschu J, Gallati H, Bartmenn P, Pohlandt F. Interleukin-6: a sensitive parameter for the early diagnosis of neonatal bacterial infection.  Pediatrics. 1994;  93 54-58
• 29 Messer J, Eyer D, Donato L, Gallati H, Matis J, Simeoni U. Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal sepsis.  J Pediatr. 1996;  129 574-580
• 30 Dammann O, Phillips T M, Allred E N et al.. Mediators of fetal inflammation in extremely low gestational age newborns.  Cytokine. 2001;  13 234-239
• 31 Woodward L J, Anderson P J, Austin N C, Howard K, Inder T E. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants.  N Engl J Med. 2006;  355 685-694
• 32 Roelants-van Rijn A M, Groenendaal F, de Vries L S. Parenchymal brain injury in the preterm infant: comparison of cranial ultrasound, MRI and neurodevelopmental outcome.  Neuropediatrics. 2001;  32 80-89
• 33 Bass W T, Jones M A, White L E et al.. Ultrasonographic differential diagnosis and neurodevelopmental outcome of cerebral white matter lesions in premature infants.  J Perinatol. 1999;  19 330-336
• 34 Back S A. Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms.  Ment Retard Dev Disabil Res Rev. 2006;  12 129-140
• 35 Lemons J A, Bauer C R, Oh W et al.. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through 1996. NICHD Neonatal Research Network.  Pediatrics. 2001;  107 E1
• 36 Maalouf E F, Philip J D, Counsell S J et al.. Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants.  Pediatrics. 2001;  107 719-727