Abstract
IL-8/CXC ligand (CXCL) 8 is ingested in high concentrations by the human fetus/neonate with amniotic fluid and human milk, and is also produced constitutively by intestinal epithelial cells (IEC). We have shown that recombinant human IL-8/CXCL8 (rhIL-8/CXCL8) protects cultured IEC against tumor necrosis factor (TNF)-α and cycloheximide-induced cytotoxicity. In view of its constitutive production, we hypothesized that IL-8/CXCL8 might play an autocrine role in fetal enterocyte maintenance. In this study, we measured IL-8/CXCL8 mRNA concentrations in fetal intestine (11–22 wk gestation), sought the presence of the protein by immunohistochemistry in fetal stomach and intestine (9–24 wk), measured IL-8/CXCL8 in neonatal gastric secretions, and studied constitutive and stimulated IL-8/CXCL8 expression in cultured IEC. We found that IL-8/CXCL8 is consistently transcribed and expressed in fetal intestinal tissue, in a developmentally regulated inverse relationship with gestational maturation. The cognate receptors for IL-8/CXCL8 are also expressed abundantly in the fetal intestine, and, therefore, we sought to determine whether the expressed IL-8/CXCL8 would complete an autocrine loop. Neutralization of IL-8/CXCL8 resulted in increased cell death in cultured IEC in the presence of TNF-α. This effect is specifically mediated through the CXCR2 receptors. We speculate that IL-8/CXCL8 secretion during cytotoxic stress reflects a cellular self-defense mechanism.
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Abbreviations
- IEC:
-
intestinal epithelial cell
- TNF-α:
-
tumor necrosis factor-alpha
- CXCL:
-
CXC ligand (the nomenclature “CXC” denotes the presence of a conserved tripeptide “cysteine-variable amino acid-cysteine” motif in the N-terminal loop of the chemokine)
- CXCR:
-
CXC receptor
- IRB:
-
institutional review board
- CK18:
-
cytokeratin 18
- DAPI:
-
4,6-diamdino-2-phenylindole
- NMP:
-
41/7, nuclear matrix protein 41/7
- bZIP:
-
transcription factors with a basic DNA-binding region and a leucine-zipper oligomerization domain
- C/EBP:
-
CCAAT/enhancer-binding protein
- AP-1:
-
activator protein-1
- NF-κB:
-
nuclear factor-kappa B
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Acknowledgements
The authors thank Dr. W. Allen Walker, Harvard University, for providing us with the H4 cell line. We also thank Drs. Kersti Linask, Y. Clare Zhang and Nagwa Dajani, and Leping Shen, Shayam Manisastry, Mingda Han, and Jo Pascuel for providing help and education for various laboratory techniques; Dr. Ritu Shah for her help with the experiments and the manuscript; Drs. Freddy Alvarez and Avital Leibovici for thoughtful discussions; nurses Dawn Bruton, Sue Stripling, and Debbie Patrick for their help with sample and data collection; and Ingrid Williams for managerial support.
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Supported by grants HD-01180 (D.A.C.), HL-61798 (R.D.C.), and HD-42326 (D.A.C.) from the National Institutes of Health.
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Maheshwari, A., Lacson, A., Lu, W. et al. Interleukin-8/CXCL8 Forms an Autocrine Loop in Fetal Intestinal Mucosa. Pediatr Res 56, 240–249 (2004). https://doi.org/10.1203/01.PDR.0000133196.25949.98
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DOI: https://doi.org/10.1203/01.PDR.0000133196.25949.98
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