Intestinal epithelial cells down-regulate macrophage tumor necrosis factor-alpha secretion: a mechanism for immune homeostasis in the gut-associated lymphoid tissue.
BACKGROUND
The gut lumen contains more than 10(6) organisms per gram of luminal contents. The mechanisms that limit the response of macrophages in the lamina propria to these microbial antigens are unknown, although an intrinsic defect in this mechanism may contribute to the development of inflammatory bowel disease. Intestinal epithelial cells (IEC) may play an important role in mediating tonic down-regulation of local immune cell activation. The purpose of this study was to discern whether IEC might modulate macrophage activation in response to a variety of microbial stimuli.


METHODS
Thioglycollate-elicited murine peritoneal macrophages were activated by endotoxin, zymosan, Escherichia coli, and Candida albicans in the presence or absence of IEC from the rat intestinal epithelial cell line IEC-6. Macrophage tumor necrosis factor-alpha (TNF-alpha) secretion was determined by enzyme-linked immunosorbent assay.


RESULTS
Lipopolysaccharide or zymosan-activated macrophages in coculture with IEC secreted significantly less TNF-alpha than macrophages cultured alone. The inhibitory effect of the IEC was dependent on their activation by lipopolysaccharide. Interleukin-1 alpha production was not affected. IEC-mediated suppression of macrophage TNF-alpha secretion was reversed by indomethacin but not by neutralizing antibody to TGF-beta.


CONCLUSIONS
Lipopolysaccharide-activated IEC down-regulate macrophage TNF-alpha secretion in response to microbial stimuli through a prostanoid-mediated mechanism. IEC may mediate tonic down-regulation of immune cell activation in the gut-associated lymphoid tissue and may thereby regulate local and systemic inflammatory responses.
Nathens
A B
AB
Division of General Surgery, Toronto Hospital Ontario, Canada.
Rotstein
O D
OD
Dackiw
A P
AP
Marshall
J C
JC
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006706:Homeostasis; D007107:Immune System / Q000502:physiology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008221:Lymphoid Tissue / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015054:Zymosan / Q000494:pharmacology
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D011451:Prostaglandin-Endoperoxide Synthases