Introduction
Carrageenan (CGN) is a high molecular weight sulphated polysaccharide (>200 kDa) derived from red algae (Rhodophyceae). Three main forms of CGN have been identified: kappa, iota, and lambda. They differ from each other in sulphation degree and solubility [1], [2]. Native CGN is thought to be harmless and is widely used as a food additive to improve texture. It is also used in cosmetics and pharmaceuticals. However, acid treatment at high temperature (80°C) triggers CGN hydrolysis to lower molecular weight (<50 kDa) compounds known as poligeenan or degraded CGN (dCGN). These dCGNs induce inflammation and have been widely used as models of colitis in several species, including rats [3], rabbits [4] and guinea pigs [5]. The role of dCGN as a tumor-promoting factor remains controversial [4], [6]–[8].
Although the native form is thought to be harmless for human consumption, small amounts of dCGN are probably produced by acid hydrolysis during gastric digestion [9], [10] or interaction with intestinal bacteria [11], [12]. Whereas the effects of native and dCGN on intestinal inflammation have been extensively analyzed in animal models, only few studies have been conducted using human cell lines. Recent studies have shown a link between exposure to native form CGN and IL-8 production by the human intestinal epithelial cell line, NCM460, via Nuclear Factor-κB (NF-κB) activation [13], [14]. NF-κB is a transcription factor that regulates the expression of genes associated with inflammation [15], [16].
Macrophage infiltration and accumulation is a common characteristic of intestinal diseases [17]. Macrophages represent 10% of total lamina propria cells, secrete a wide range of biologically active compounds and express cell-adhesion molecules. The immune cell response to an inflammatory stimulus seems to be amplified or directly generated by cells exposed to sulphated polysaccharides such as carrageenans. Indeed, inflammation induced by dCGN was associated with recruitment of macrophages to inflammation sites [18], [19]. Also, inflammation induced by Dextran Sulphate Sodium (DSS), another sulphated compound, was directly associated with macrophages recruitment [20], since DSS still provoked inflammation after T-lymphocyte and NK cell depletion [20]. Although inflammation can be induced by dCGN, there are no data on human monocyte responses to dCGN exposure. Therefore, to investigate the effects of dCGN on human monocytes, normal Peripheral Blood Monocytes (PBM) and tumoral monocyte/macrophage THP-1 cells were exposed to 10 kDa and 40 kDa dCGN. We found that dCGN inhibited THP-1 cell proliferation in vitro, increased ICAM-1 expression, stimulated ICAM-1-dependent monocyte aggregation, and stimulated TNF-α expression and secretion. These responses were more pronounced after 40 kDa dCGN exposure and were linked to NF-κB activation. In addition, the 40 kDa dCGN, but not the 10 kDa dCGN induced in vivo colitis as shown by the inflammatory response in the rat colon. These results suggest that the degraded forms of CGN have an important effect on monocytes resulting in an inflammatory phenotype.