Curcumin Decreases Binding of Shiga-Like Toxin-1B on Human Intestinal Epithelial Cell Line HT29 Stimulated with TNF-.ALPHA. and IL-1.BETA.: Suppression of p38, JNK and NF-.KAPPA.B p65 as Potential Targets

Abstract

(Stx)-producing Escherichia coli (STEC) is an important cause of a range of illnesses from self-limiting watery diarrhea and hemorrhagic colitis to severe conditions such as hemolytic uremic syndrome (HUS) and thrombotic thrombocytopoenic purpura. 1,2) Recent research has partially documented how and where Stx has pathogenic effects in humans. Because STEC is a noninvasive intestinal pathogen, it has been shown that Stx in host intestinal lumen must cross the intestinal epithelial cells (IECs) to cause disease in distal organs. [3][4][5][6] The extent to which Stx is absorbed systemically may influence who is at risk for serious complications of the infection. Because the IECs are the first line in contact with Stx in a host, the interaction of Stx with epithelium may be a pivotal role in HUS 3) through induction of apoptosis in vivo and in vitro studies.7-10) Apoptosis of IECs could destroy the barriers in host lumen and permit Stx to enter the bloodstream and attack the central nervous and/or renal systems. 5,11) In many cells, Stx-induced apoptosis has been induced by cleavage of poly(ADP-ribose) polymerase, release of cytochrome C and capase-3 activities with mitogen-activated protein kinases (MAPKs).12,13) Some researchers have also suggested that the apoptosis involves a rapid, sustained increase in intracellular Ca 2ϩ concentration, a transient increase in cAMP levels, protein kinase A activation and ceramide accumulation.14,15) Furthermore, it was reported that the up-regulation of Stx-receptor increases high renal cell sensitivity to the cytotoxic effects of Stx. 16)Stx binds to cell-surface glycosphingolipids, terminating in galactose-a1,4-galactose, whereupon the complex is internalized, with resultant inhibition of peptide elongation. 2,17)The major glycosphingolipid that binds Stx-1 is galactosea1,4-galactose-b1,4-glucose ceramide (globotriaosylceramide: Gb3). These toxins are structurally similar heterodimers composed of one enzymatically active A subunit 18) that irreversibly inhibits protein synthesis by means of its Nglycosidase activity on ribosomal subunit and B subunit pentamers that binds Gb3. 19,20) TNF-a or IL-1b have been also known to be important cytokines to induce Gb3 to sensitivity of Stx.14-16) Therefore, we assume that down-regulation of Gb3 synthase decreases the sensitivity to the cytotoxicity of Stx.Curcumin has been shown to exhibit anti-inflammatory and anti-mutagenic activities, 21,22) the inhibition of chemical carcinogen-induced tumor formation in mice 23,24) and the anti-proliferation of various cultured tumor cells.25,26) Our previous study has also shown that curcumin significantly inhibited LPS-induced immunostimulation of murine dendritic cells through inhibition of MAPKs and NF-kB.27) These potent chemopreventive activities of curcumin may be attributed to the inhibition of certain signal transduction pathways critical to tumor cell growth, such as AP-1, NF-kB, MAPKs and protein kinase C. [28][29][30] However Gb3 expression by curcumin is not understood at all in IECs...

Role of the JNK signal transduction pathway in inflammatory bowel disease

“…Phospho-JNK was present in the intestinal cells, macrophages and lymphocytes, localized pre-dominantly in the nucleus. These findings validated the results from in-vitro cell culture studies [14] . Interestingly, increased JNK activation has also been shown in steroidresistant patients [15] .…”

Multi‐targeted therapy by curcumin: how spicy is it?

“…Studies performed in cultured HT29 intestinal epithelial cells stimulated with TNF-a and IL1ß showed that curcumin could block the binding of Shiga-like toxins (Stx) to intestinal epithelial cells by inhibiting Gb3 synthase (GalT6) mRNA expression [67]. In another set of experiments, three major active principles isolated from the crude methanol extract of the rhizomes of Curcuma zedoaria [1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one, procurcumenol, and epiprocurcumenol] were reported to suppress the production of TNF-a in LPS-stimulated macrophages [75].…”

Effects of curcumin on Helicobacter pylori infection

“…Numerous studies have reported that curcumin has a wide range of biological activities including antimicrobial, antioxidant, antitumor (10), and anti-inflammatory effects. In addition, curcumin has some immunosuppressive activities (11) including expression of cytokines such as IL-1 and TNF-α (12,13). On the other hand, curcumin enhanced phagocytic activity of macrophages (14).…”