Regulation of α 1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells

• Published in: Clinical and experimental immunology 2002-05, Vol.128 (2), p.279-284
• Main Authors: FAUST, D, RASCHKE, K, HORMANN, S, MILOVIC, V, STEIN, J
• Format: Article
• Language: English
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1046/j.1365-2249.2002.01843.x

α1-Proteinase inhibitor (α1-PI) is the main serine proteinase inhibitor in human plasma. Apart from its synthesis in the liver, this anti-inflammatory protein is also synthesized by and excreted from human intestinal epithelial cells. Antiinflammatory actions of α1-PI are thought to be of relevance in the pathogenesis of inflammatory bowel disease. To investigate the role of macrophage-derived cytokines on α1-PI secretion from intestinal epithelial cells, we cultured Caco-2 cells until differentiation (14 days in culture) on permeable filter supports. Monolayers of differentiated Caco-2 cells were then co-cultured with human peritoneal macrophages, grown on plastic in the basolateral chamber. Under these conditions, α1-PI secretion from Caco-2 cells was enhanced by 45%, probably by a direct action of macrophage-derived cytokines on Caco-2 cells. To extend this observation further, we treated differentiated Caco-2 cells with macrophage-derived proinflammatory cytokines (IL-1β, IL-8, TNF-α), as well as with lymphocyte-derived cytokines IL-2, IL-6 and IFN-γ. As early as after 24h treatment, IL-2 and IL-8 induced a significant and dose-dependent increase of α-1-PI secretion into cell culture medium; this effect was completely reversed after immunoneutralization by the antibodies against IL-2 and IL-8 α1-PI secretion was only slightly decreased after treatment with IFN-γ, while IL-1β, IL-6 and TNF-α had no effect. α1-PI secretion correlated well with the expression of this protein in differentiated Caco-2 cells after cytokine treatment, as confirmed by Western blot. Our data imply that, in vitro, α1-PI secretion in enterocyte-like Caco-2 cells is up-regulated by IL-2 and IL-8. Our results suggest that both lymphocyte- and macrophage-derived cytokines regulate secretion of the anti-inflammatory protein α1-PI in intestinal epithelial cells.