Characterization of the Pro-Inflammatory Cytokine IL-1[beta] on Butyrate Metabolism in Colorectal Cancer Cells

Genetic and environmental factors impact colorectal cancer incidence [2, 3]. Environmental factors include fiber intake and exercise, which are both postulated to reduce colorectal cancer risk [4-6]. While much is understood in regards to how fiber and its derived nutrients influence inflammation; little is known about how inflammation influences how nutrient impact cell metabolism and physiology.

The short chain fatty acid butyrate, is derived from the fermentation of fiber in the colon and is the preferred energy substrate for colonic epithelial cells (colonocytes) [7, 8]. Butyrate also slows cell proliferation in cancerous colonocytes through its ability to inhibit histone deacetylases (HDACs) [20]. HDACs are enzymes that remove acetyl groups from histones [9]. Inhibition of HDACs results in hyperacetylation, which leads to changes in gene expression [10]. In cancerous colonocytes, inhibition of HDACs by butyrate induces cell cycle arrest, in part, via increased p21 expression [10]. Cancer cells deficient in p21 have been reported to be resistant to butyrate’s anti-cancer effects [11]. Thus, blocking p21 induction by butyrate would promote tumor development and may exclude the beneficial effect derived from a high fiber diet toward prevention of the disease.

Patients with colorectal cancer have elevated serum levels of pro-inflammatory cytokines [12-14]. Pro-inflammatory cytokines have been shown to suppress butyrate metabolism in cancerous colonocytes [18]. In addition, colorectal cancer patients have a significant reduction in butyrate producing bacteria [15-17]. The significance of this reduction is unclear, however, taken in conjunction with decreased butyrate metabolism it is likely to impact of butyrate’s antiproliferation activity in the colon.

Identification of mechanisms that mediate decreased butyrate metabolism may aid in the understanding of fiber’s role in colorectal cancer. Here, we find that IL-1[beta] dampens butyrate metabolism in colorectal cancer cells. Furthermore, IL-1[beta] decreases butyrate’s ability to slow cell proliferation. We identify two mechanisms by which IL-1[beta] induces these effects. First, we determine that IL-1[beta] is operating through its receptor, IL-1RI, and second through a p38-mediated mechanism. These findings are consistent with previous reports that proinflammatory cytokines promote cancer cell survival and proliferation [19-22].