Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium

Abstract

In inflammatory bowel diseases (IBD), intestinal barrier function is impaired as a result of deteriorations in epithelial tight junction (TJ) structure. IL-6, a pleiotropic cytokine, is elevated in IBD patients, although the role of IL-6 in barrier function remains unknown. We present evidence that IL-6 increases TJ permeability by stimulating the expression of channel-forming claudin-2, which is required for increased caudal-related homeobox (Cdx) 2 through the MEK/ERK and PI3K pathways in intestinal epithelial cells. IL-6 increases the cation-selective TJ permeability without any changes to uncharged dextran flux or cell viability in Caco-2 cells. IL-6 markedly induces claudin-2 expression, which is associated with increased TJ permeability. The colonic mucosa of mice injected with IL-6 also exhibits an increase in claudin-2 expression. The claudin-2 expression and TJ permeability induced by IL-6 are sensitive to the inhibition of gp130, MEK, and PI3K. Furthermore, expression of WT-MEK1 induces claudin-2 expression in Caco-2 cells. Claudin-2 promoter activity is increased by IL-6 in a MEK/ERK and PI3K-dependent manner, and deletion of Cdx binding sites in the promoter sequence results in a loss of IL-6-induced promoter activity. IL-6 increases Cdx2 protein expression, which is suppressed by the inhibition of MEK and PI3K. These observations may reveal an important mechanism by which IL-6 can undermine the integrity of the intestinal barrier.

Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function

“…Similarly, Trem-1 + macrophages and intestinal epithelial cells have been shown to be major sources of IL-6 in Crohn's disease, and elevated IL-6 levels have been demonstrated in serum and tissue of IBD patients. Recently, it was shown that IL-6 regulates Claudin-2 expression and permeability in cultured intestinal epithelial cells, establishing a clear link between localised inflammation and intestinal permeability [7]. In our study, we could indeed confirm that activated intestinal macrophages were the major source of IL-6 and NO in cirrhosis, suggesting that these cells may be capable of producing factors that influence intestinal permeability.…”

“…The expression and turnover of TJ proteins are influenced by inflammation and oxidative stress [6,7].…”

Autophagy Enhances Intestinal Epithelial Tight Junction Barrier Function by Targeting Claudin-2 Protein Degradation

“…Several studies have shown that the inflamed intestinal mucosa in patients with active IBD has increased claudin-2 expression. Moreover, inflammatory cytokines whose levels are increased markedly in IBD patients, including TNF-␣, IL-13, IL-17, and IL-6, cause an increase in claudin-2 expression and a claudin-2-dependent increase in TJ permeability (43)(44)(45)(46)(47). Therefore, the role of claudin-2 in intestinal pathological processes has been attributed, in part, to increases in intestinal TJ permeability.…”

[Ca2+] Oscillations and IL-6 Release Induced by α-Hemolysin from Escherichia coli Require P2 Receptor Activation in Renal Epithelia

“…Here interaction with the epithelial barrier is likely to take precedence. In this context, it is interesting that both E. coli (46) and aerolysin from Aeromonas hydrophila have been shown to modify tight junctions (47) and several cytokines including IL-6 have indeed been shown to modulate the expression pattern of occludins and claudins as well as modulate tight junctional function in certain epithelia/ endothelia (48,49). Thus, it is likely that HlyA and the following ATP-dependent cytokine release may interfere with the barrier function of the epithelia and thus, its ability to keep the bacteria from invasion.…”