Interleukin-8/CXCL8 forms an autocrine loop in fetal intestinal mucosa

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)-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.