Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: Potential contributors to IBD-associated diarrhea

Autor: Mary L. Harris, Laurie S. Conklin, Philip Alex, Lisa W. Datta, Xuhang Li, Christine A. Iacobuzio-Donahue, Steven R. Brant, Mark Donowitz, Nicholas C. Zachos, Yueping Chen, Carmen Cuffari, Sean Sullivan, Themos Dassopoulos
Rok vydání: 2009
Předmět:
Zdroj: Inflammatory Bowel Diseases. 15:261-274
ISSN: 1078-0998
Popis: Inflammatory bowel diseases (IBD) are generally classified into two subtypes: Crohn's disease (CD) and ulcerative colitis (UC) (37). Diarrhea is one of the most common symptoms among patients with IBD (21). Decreases in Na+ absorption and increases in Cl- secretion, resulting in impaired water transport, are thought to be the main electrolyte transport abnormalities in IBD-associated diarrhea (21;40). Other mechanisms contributing to diarrhea in IBD include short bowel, ileal disease (e.g. bile salt malabsorption), fistulae, maldigestion and bacterial overgrowth (45). Some of the earliest data supporting a role of dysregulated electrolyte transporters in IBD-associated diarrhea came from the observations that the levels of Na+ and Cl- in the stool of Crohn's colitis were elevated while stool pH was lower than that of control subjects (24;25). IBD-associated diarrhea has also been attributed to elevated pro-inflammatory cytokines (which inhibit Na+ transport), such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and various interleukins (IL), including IL-4,6,8,12, & 13 (3-6;13;39;44) (see more details in Table S1). For example, IFN-γ inhibits intestinal transport by down-regulating Na+/K+-ATPase and Na+/K+/2Cl- (6). In rat intestine and intestinal epithelial cell models, TNF-α and IFN-γ down-regulate NHE3 (4;39). TNF-α inhibits NHE3 activity by increasing NHE3 internalization (13). In both DSS- and TNBS-induced mouse colitis models, we recently demonstrated that diarrhea were associated with significant elevation of various cytokines in colonic mucosa (1): In the acute DSS colitis model, Th1-Th2 cytokines (IL-6, IFNγ, and IL-17) were increased while Th1-Th17 cytokines (IL-12p40, IL-23p19, IFNγ, and IL-17) were up-regulated in acute TNBS colitis. In chronic colitis models, IL-6 and IFNγ (but not IL-12p40 &IL-17) were elevated in DSS colitis, while IL-12p40, IL-17, and particularly IL-IL23p19 were greatly increased in TNBS colitis. These data suggest that, although there are clear differences in the production of specific cytokines between the UC-like (DSS model) and CD-like (TNBS model), these cytokine differences result in a similar clinical consequence: diarrhea (1). In addition, NHE3 activity in Caco-2 cells was inhibited in a dose-dependent fashion by nitric oxide (NO), over-production of which has been suggested to be involved in the pathogenesis of IBD (16). NHE3 plays a critical role in normal intestinal electro-neutral NaCl absorption, inhibition of which is an important mechanism for diarrheal diseases (15). In addition to active electrolyte transport across intestinal epithelial cells, altered epithelial paracellular permeability was also observed in IBD patients and associated with relapsing diarrhea (8;36). Proinflammatory cytokines disrupt epithelial barrier functions by either decreasing expression and/or causing mis-localization of tight-junction (TJ) complex proteins (11;23). Thus, impaired electrolyte transport, either transcellularly or paracellularly, contributes to IBD-associated diarrhea. Down- or up-regulation of several membrane transporters in different models have been linked to IBD-associated diarrhea, including Na+/K+-ATPase (6;36;44), Na+ channel (ENaC) (3), Na+/H+ exchangers 1 &3 (NHE1 &3; in cell models only) (4;13;39), and Na+/K+/2Cl- (3;6) (see extensive list of transporters and relevant references in Suppl Table S1; S: Supplementary Data). While previous studies have enhanced our understanding of IBD-associated diarrhea, changes of epithelial transporters in cell culture or animal models may or may not reflect the changes in intestinal mucosa of IBD patients. In addition, previous human studies examined primarily the changes of transporter mRNA levels, which may or may not correlate with the changes at the protein levels of these transporters, the latter of which are much more reliable indicators for actual transport activity. Therefore, it is necessary to examine at the protein levels the changes in expression of relevant transporter in intestinal mucosa from IBD patients, and correlate them to disease activity. Here, we present data showing a coordinated down-regulation of Na+-related transporter proteins in both patients with active IBD and mice with well-established acute colitis induced by DSS or TNBS. Our data suggest that a common regulatory mechanism may exist to systematically down-regulate multiple intestinal Na+ transporters and functionally related proteins that are involved in intestinal Na+-absorption.
Databáze: OpenAIRE
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