Ulcerative colitis (UC) is the result of an inappropriate colonic inflammatory response triggered by environmental and genetic factors. We have recently shown that mucus from UC patients has a decreased phosphatidylcholine (PC) content, while clinical trials revealed that therapeutic addition of PC to the colonic mucus alleviated the inflammatory activity. The mechanisms behind this are still unclear. We hypothesized that PC has at least two possible functions in the intestine: First, it establishes the surface hydrophobicity of the mucus and therefore protects the underlying tissue against intraluminal aggressors; recent experiments on surgical specimens revealed reduced surface tension and hydrophobicity in UC patients. Second, mucus phospholipids might also be integrated into the plasma membranes of enterocytes and thereby influence the signaling state of the mucosa. PC has been shown to inhibit TNF-α induced pro-inflammatory responses including: (1) assembly of plasma membrane actin; (2)？activation of MAP kinases ERK and p38; and (3) activation of NF-κB and synthesis of pro-inflammatory gene products. Other phospholipids like phosphatidylethanolamine or sphingomyelin ？had no effect. PC also inhibited latex bead phagosome actin assembly, killing of M. tuberculosis in macrophages, and sphingosine-1-phosphate induced actin assembly in macrophages. Collectively, these results provide a molecular foundation that shows PC, firstly, as an anti-inflammatory, and secondly, as a surface hydrophobicity increasing compound with promising therapeutic potential in the treatment of inflammatory bowel disease.
Eros, G; Varga, G; Varadi, R; Czobel, M; Kaszaki, J; Ghyczy, M; Boros, M. Anti-inflammatory action of a phosphatidylcholine, phosphatidylethanolamine and N-acylphosphatidylethanolamine-enriched diet in carrageenan-induced pleurisy. Eur. Surg. Res？2009, 42, 40–48.
Zhou, Y; Dial, EJ; Doyen, R; Lichtenberger, LM. Effect of indomethacin on bile acid-phospholipid interactions: Implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs. Am. J. Physiol. Gastrointest. Liver Physiol？2010, 298, G722–G731.
Lugea, A; Antolin, M; Mourelle, M; Guarner, F; Malagelada, JR. Deranged hydrophobic barrier of the rat gastroduodenal mucosa after parenteral nonsteroidal anti-inflammatory drugs. Gastroenterology？1997, 112, 1931–1939.
Lichtenberger, LM; Romero, JJ; Dial, EJ. Gastrointestinal safety and therapeutic efficacy of parenterally administered phosphatidylcholine-associated indomethacin in rodent model systems. Br. J. Pharmacol？2009, 157, 252–257.
Lanza, FL; Marathi, UK; Anand, BS; Lichtenberger, LM. Clinical trial: Comparison of ibuprofen-phosphatidylcholine and ibuprofen on the gastrointestinal safety and analgesic efficacy in osteoarthritic patients. Aliment Pharmacol. Ther？2008, 28, 431–442.
Rutgeerts, P; Goboes, K; Peeters, M; Hiele, M; Penninckx, F; Aerts, R; Kerremans, R; Vantrappen, G. Effect of faecal stream diversion on recurrence of Crohn's disease in the neoterminal ileum. Lancet？1991, 338, 771–774.
Duchmann, R; May, E; Heike, M; Knolle, P; Neurath, M; Meyer zum Buschenfelde, KH. T cell specificity and cross reactivity towards enterobacteria, bacteroides, bifidobacterium, and antigens from resident intestinal flora in humans. Gut？1999, 44, 812–818.
Einerhand, AW; Renes, IB; Makkink, MK; van der Sluis, M; Buller, HA; Dekker, J. Role of mucins in inflammatory bowel disease: Important lessons from experimental models. Eur. J. Gastroenterol. Hepatol？2002, 14, 757–765.
Ehehalt, R; Wagenblast, J; Erben, G; Lehmann, WD; Hinz, U; Merle, U; Stremmel, W. Phosphatidylcholine and lysophosphatidylcholine in intestinal mucus of ulcerative colitis patients. A quantitative approach by nanoElectrospray-tandem mass spectrometry. Scand. J. Gastroenterol？2004, 39, 737–742.
Longman, RJ; Poulsom, R; Corfield, AP; Warren, BF; Wright, NA; Thomas, MG. Alterations in the composition of the supramucosal defense barrier in relation to disease severity of ulcerative colitis. J. Histochem. Cytochem？2006, 54, 1335–1348.
Langmann, T; Moehle, C; Mauerer, R; Scharl, M; Liebisch, G; Zahn, A; Stremmel, W; Schmitz, G. Loss of detoxification in inflammatory bowel disease: Dysregulation of pregnane X receptor target genes. Gastroenterology？2004, 127, 26–40.
Fabia, R; Ar'Rajab, A; Willen, R; Andersson, R; Ahren, B; Larsson, K; Bengmark, S. Effects of phosphatidylcholine and phosphatidylinositol on acetic-acid-induced colitis in the rat. Digestion？1992, 53, 35–44.
Gutierrez, MG; Gonzalez, AP; Anes, E; Griffiths, G. Role of lipids in killing mycobacteria by macrophages: Evidence for NF-kappaB-dependent and -independent killing induced by different lipids. Cell Microbiol？2009, 11, 406–420.
Parlesak, A; Schaeckeler, S; Moser, L; Bode, C. Conjugated primary bile salts reduce permeability of endotoxin through intestinal epithelial cells and synergize with phosphatidylcholine in suppression of inflammatory cytokine production. Crit. Care Med？2007, 35, 2367–2374.
Dial, EJ; Tran, DM; Romero, JJ; Zayat, M; Lichtenberger, LM. A direct role for secretory phospholipase A2 and lyso-phosphatidylcholine in the mediation of lipopolysaccharide-induced gastric injury. Shock？2010, 33, 634–638.
Braun, A; Schoenfeld, U; Welsch, T; Kadmon, M; Funke, B; Autschbach, F; Grunze, M; Stremmel, W; Kienle, P; Ehehalt, R. The surface hydrophobicity of the colonic mucosa is reduced in ulcerative colitis. J. Crohn's Colitis？2010, 4, S13–S120.
Triantafilou, M; Morath, S; Mackie, A; Hartung, T; Triantafilou, K. Lateral diffusion of Toll-like receptors reveals that they are transiently confined within lipid rafts on the plasma membrane. J. Cell Sci？2004, 117, 4007–4014.
Nishida, T; Miwa, H; Shigematsu, A; Yamamoto, M; Iida, M; Fujishima, M. Increased arachidonic acid composition of phospholipids in colonic mucosa from patients with active ulcerative colitis. Gut？1987, 28, 1002–1007.
Ehehalt, R; Braun, A; Karner, M; Fullekrug, J; Stremmel, W. Phosphatidylcholine as a constituent in the colonic mucosal barrier--physiological and clinical relevance. Biochim. Biophys. Acta？2010, 1801, 983–993.
Takaku, K; Sonoshita, M; Sasaki, N; Uozumi, N; Doi, Y; Shimizu, T; Taketo, MM. Suppression of intestinal polyposis in Apc(delta 716) knockout mice by an additional mutation in the cytosolic phospholipase A(2) gene. J. Biol. Chem？2000, 275, 34013–34016.