High-level expression of IkB-b in the surface epithelium of the colon: in vitro evidence for an immunomodulatory role

Abstract

The intestinal epithelium is spatially segregated into two compartments, one containing undifferentiated cells in a proliferative state and one with non-proliferative differentiated cells. Although this epithelium can produce many immunemodulating substances, emerging evidence suggests that the differentiated cell compartment is less immune responsive. Indeed, it is the differentiated cellular compartment that represents the interface between the highly antigenic luminal environment and the mucosal immune system. The NF-B/rel family of transcriptional activators play a critical role in regulating the inflammatory response by activating a wide variety of immune-modulating genes. These transcription factors are maintained in an inactive state in the cytoplasmic compartment by interaction with inhibitory proteins of the I B family. In this study we show by immunohistochemistry that I B-␤ is expressed at high levels specifically in the differentiated surface epithelium of the colonic mucosa. Using a naturally occurring compound found in the colon of vertebrates, butyrate, we provide evidence in an intestinal cell line that alteration of I B-␤ expression can modulate the transcriptional activation of the interleukin-8 (IL-8) gene by preventing the nuclear translocation of NF-B proteins. Therefore, the expression of I B-␤ in the differentiated surface epithelium of the colon may help these cells act as an immunological barrier to prevent activation of the mucosal immune system.

Butyrate Suppression of Colonocyte NF-κB Activation and Cellular Proteasome Activity

“…Interestingly, NF-B inhibition by butyrate has been observed in Caco-2 cells without any apparent change in IB-␣ degradation (24). Butyrate does, however, increase IB-␤ levels in Caco-2 cells without affecting IB-␤ mRNA levels (24). This response may be due in part to an enhanced stabilization of the IB-␤ protein through a decrease in cellular proteasome activity.…”

“…The increase in IB-␣ stability reported by other groups may also be the result of a lower proteasome activity in butyratetreated cells. Interestingly, NF-B inhibition by butyrate has been observed in Caco-2 cells without any apparent change in IB-␣ degradation (24). Butyrate does, however, increase IB-␤ levels in Caco-2 cells without affecting IB-␤ mRNA levels (24).…”

“…2B is a DNA competition analysis, which demonstrated that the protein⅐DNA complex inhibited by butyrate is a specific NF-B complex. The butyrate suppression of NF-B DNA binding activity is reflected in a reduced level of NF-B-regulated gene expression (24,25).…”

“…In addition, a number of transcription factors are directly regulated by acetylation, and butyrate can enhance their activity (including GATA-1 and p53) (18 -21). We and others have reported that butyrate can modulate the activity of the transcription factor NF-B in a number of different cell types including colon cancer cell lines, cells isolated from the lamina propria of the colon, and macrophages (22)(23)(24)(25). The ability of butyrate to modulate NF-B activity may arise from its ability to inhibit protein deacetylases.…”

Intraperitoneal administration of butyrate prevents the severity of acetic acid colitis in rats

“…Much as butyrate tends to impart a protective effect, several authors have indicated failures or limited success of butyrate to relieve IBD patients (Harig et al, 1989;Sanderson, 1997;Hamer et al, 2010b). One of the proposed reasons includes presence of IL-8 in the intestinal mucosa, which is either activated (Fusunyan et al, 1998; or inhibited (Huang et al, 1997;Wu et al, 1999) by different doses of butyrate (Malago et al, 2005). Thus high concentrations of butyrate correlate with elevated IL-8 levels in the intestinal mucosa of IBD patients (Dabard et al, 1987;Treem et al, 1994) whereas low levels diminish the disease activity (O'Morain et al, 1984).…”