Mulligan, P.; White, N.R.J.; Monteleone, G.; Wang, P.; Wilson, J.W.; Ohtsuka, Y.; Sanderson, I.R.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA58
Academic Journal
We hypothesised that lactoferrin (LF) alters the expression of immune genes in the infant intestine by binding to DNA. We examined both the direct and indirect effects on immune gene regulation of its binding to DNA. Two biologically relevant compartments were studied: binding to pro-inflammatory, bacterial DNA sequences (CpG motifs) in the extracellular environment, and binding to gene promoters in the cell nucleus. LF inhibited CpG motifiinduced NF-κB activation and IL-8 and IL-12 gene transcription in B-cells at LF concentrations greater than 0.5 µM. However, the intestinal epithelial cell lines, Caco-2 and HT-29, were unresponsive to CpG motifs under a variety of conditions. Using three independent techniques, we demonstrated that LF does not regulate reporter gene transcription, nor does it bind specifically to putative DNA response elements. We conclusively showed no LF Iocalisation into enterocyte and lymphocyte nuclei by tagging the LF with green fluorescent protein. Purification of intact, DNA-binding LF from the urine of preterm infants has been previously described, indicating significant survival and transcytosis or leakage of LF across the infant intestine. This suggests that lymphocytes in the lamina propria and Peyer's patches of the infant intestine are exposed to high concentrations of LF. We conclude that DNA binding by LF extracellularly, but not in the nucleus, is an important mechanism of immune gene regulation. Such a mechanism is likely to function in B-cells exposed to bacterial DNA in the lamina propria and Peyer's patches of the breast-fed infant.


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