Interleukin-8/CXCL8 forms an autocrine loop in fetal intestinal mucosa.
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)-alpha 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-alpha. 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.
Maheshwari
Akhil
A
Division of Neonatology, Department of Pediatrics, University of South Florida College of Medicine, Tampa, FL, USA. Akhil@peds.uab.edu
Lacson
Atilano
A
Lu
Wenge
W
Fox
Samuel E
SE
Barleycorn
Aaron A
AA
Christensen
Robert D
RD
Calhoun
Darlene A
DA
D019898:Autocrine Communication; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival; D053938:DNA Fragmentation; D005260:Female; D005333:Fetus / Q000033:anatomy & histology* / Q000502:physiology*; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016209:Interleukin-8; D012333:RNA, Messenger; D023062:Receptors, Interleukin-8A; D014409:Tumor Necrosis Factor-alpha