Regulation ofα1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells

Abstract

SUMMARYa1-Proteinase inhibitor (a1-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 a1-PI are thought to be of relevance in the pathogenesis of inflammatory bowel disease. To investigate the role of macrophage-derived cytokines on a1-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, a1-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-1b, IL-8, TNF-a), as well as with lymphocyte-derived cytokines IL-2, IL-6 and IFN-g. As early as after 24 h treatment, IL-2 and IL-8 induced a significant and dose-dependent increase of a-1-PI secretion into cell culture medium; this effect was completely reversed after immunoneutralization by the antibodies against IL-2 and IL-8 a1-PI secretion was only slightly decreased after treatment with IFN-g, while IL-1b, IL-6 and TNFa had no effect. a1-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, a1-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 a1-PI in intestinal epithelial cells.

Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells

“…Presumably, this increase results in the inhibition of neutrophil elastase, which breaks down connective tissue components causing tissue damage during inflammatory diseases. It has been suggested that extrahepatic α1-PI may also contribute locally, within specific organs, to the response initiated by an inflammatory or infectious process [14,41]. Our study extends this possibility to human pancreatic islets, raising the question of whether α1-PI is implicated in the protection of peripherally located islet cells, which are preferentially exposed to the autoimmune attacks leading to islet destruction.…”

Intestinal proteome changes during infant necrotizing enterocolitis

“…Intestinal proteomics of NEC patients small intestine and colon could protect the intestinal mucosa from the ongoing inflammation damage, similar to its role in inflammatory bowel diseases (11). Two HSPs (HSPA5 and HSP27) were affected by the progression of NEC lesions in the small intestine as detected by proteomic analysis.…”

Proteomic Analysis Reveals Field-Wide Changes in Protein Expression in the Morphologically Normal Mucosa of Patients with Colorectal Neoplasia

“…API has previously been shown to be synthesized by hepatocytes, macrophages, and intestinal epithelial cells (27), and gastric cancer has been reported to be associated with high levels of API in the gastric juice (28). It is also detectable in the feces of both healthy subjects and patients with inflammatory bowel disease (29), and in vitro evidence suggests that it is secreted in response to certain proinflammatory cytokines (30). There are also reports suggesting that high levels of API expression in sporadic colorectal tumors are associated with poor prognosis (31).…”