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272 POLYMORPHONUCLEAR LEUKOCYTES ISOLATED FROM CORD BLOOD OF PREMATURELY BORN INFANTS RESPOND TO PLATELET-ACTIVATING FACTOR WITH DIFFERENTIAL GENE EXPRESSION
  1. F. J. Rubner,
  2. M. M. Denis
  1. A. Lowichik, K.H. Albertine

Abstract

Platelet-activating factor (PAF) is implicated in inflammatory diseases of premature infants such as necrotizing enterocolitis (NEC). Polymorphonuclear leukocytes (PMN) bear the receptor for PAF, and release preformed inflammatory mediators upon stimulation. In PAF-stimulated adult PMNs, both retinoic acid receptor alpha (RARα) and interleukin-6 receptor alpha (IL-6Rα) are rapidly induced in a translationally regulated manner via mammalian target of rapamycin (mTOR) pathway. Expression of RARα mediates the anti-inflammatory effects of retinoic acid, the physiologic metabolite of vitamin A, and decreases IL-8 synthesis in PAF-stimulated adult PMNs treated with retinoic acid. Expression of IL-6Rα mediates resolution of acute inflammation or aids in the transition to chronic inflammation. Whether these anti-inflammatory mediators are induced by PAF stimulation in PMNs isolated from preterm infants is unknown. We therefore hypothesized that expression of RARα and IL-6Rα protein in PMNs isolated from preterm infants would be differentially regulated when compared to adult PMNs or PMNs isolated from term infants. Human PMNs isolated from adult, term infants and preterm infants were stimulated with PAF [10-8M] for 30 min - 4 hours. Western blotting showed a time dependent RARα and IL-6Rα protein induction in term and adult PMNs with little or no detectable expression at baseline. While PMNs isolated from preterm infants expressed no RARα at baseline, RARα protein induction by PAF was attenuated. Furthermore, these cells expressed IL-6Rα at baseline, and showed decreased expression of IL-6Rα following PAF stimulation. Pathologic gastrointestinal specimens of control and surgically treated patients with NEC were immunohistochemically stained for RARα and IL-6Rα expression. PMNs visualized in NEC tissue specimens expressed both RARα and IL-6Rα, and while fewer PMNs were seen in the control specimens, both RARα and IL-6Rα staining was detectable. We conclude that RARα and IL-6Rα expression is differentially regulated in PMNs isolated from preterm infants compared to PMNs from term infants and adults, and that both proteins are expressed in PMNs isolated from pathologic specimens of premature infants treated surgically for NEC. We speculate that decreased expression of these proteins may predispose PMNs isolated from prematurely born infants to a pronounced pro-inflammatory response and may participate in the pathogenesis of inflammatory diseases of the neonate.

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