Proinflammatory cytokines TNF-alpha and IFN-gamma alter laminin expression under an apoptosis-independent mechanism in human intestinal epithelial cells.
Laminins are basement membrane molecules that mediate cell functions such as adhesion, proliferation, migration, and differentiation. In the normal small intestine, laminin-5 and -10 are mainly expressed at the base of villus cells. However, in Crohn's disease (CD), a major redistribution of these laminins to the crypt region of the inflamed ileal mucosa has been observed, suggesting a possible relationship between laminin expression and cytokine and/or growth factor production, which is also altered in CD. The aim of this study was to test the hypothesis that proinflammatory cytokines can modulate laminin expression by intestinal epithelial cells. The effect of TNF-alpha, IFN-gamma, IL-1beta, IL-6, and transforming growth factor (TGF)-beta was analyzed on the expression of laminins in the normal human intestinal epithelial crypt (HIEC) cell line. When treated with a single cytokine, HIEC cells secreted small amounts of laminin-5 and -10. Only TNF-alpha and TGF-beta induced a slight increase in the secretion of these laminins. However, in combination, TNF-alpha and IFN-gamma synergistically stimulated the secretion of both laminin-5 and -10 in HIEC cells. Transcript analyses suggested that the upregulation of the two laminins might depend on distinct mechanisms. Interestingly, the TNF-alpha and IFN-gamma combination was also found to significantly promote apoptosis. However, the effect of cytokines on the secretion of laminins was maintained even after completely blocking apoptosis by inhibiting caspase activities. These results demonstrate that laminin production is specifically modulated by the proinflammatory cytokines TNF-alpha and IFN-gamma in intestinal epithelial cells under an apoptosis-independent mechanism.
Francoeur
Caroline
C
Canadian Institutes of Health Research Group in Functional Development and Physiopathology of the Digestive Tract, Département d'anatomie et de biologie cellulaire, Faculté de médecine, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
Escaffit
Fabrice
F
Vachon
Pierre H
PH
Beaulieu
Jean-François
JF
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000166:cytology* / Q000187:drug effects; D007797:Laminin / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D061945:Caspase Inhibitors; D017931:DNA Primers; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D007797:Laminin; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma