5-Lipoxygenase modulates colitis through the regulation of adhesion molecule expression and neutrophil migration.
Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes makes it as therapeutic target for inflammatory conditions like inflammatory bowel disease (IBD). In the present study, by comparing the responses in wild-type mice (5-LOWT) and mice lacking the 5-lipoxygenase (5-LOKO), we investigated the role played by this enzyme in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated 5-LOWT mice, DNBS-treated 5-LOKO mice experienced a reduced rate of the extent and severity of the histological signs of colon injury. After administration of DNBS 5-LOWT mice showed hemorrhagic diarrhea, weight loss and large areas of necrosis in the mucosa of the colon. Neutrophil infiltration was associated with the expression of ICAM-1, VCAM-1, P-selectin, E-selectin that were mainly localized around vessels. Absence of a functional 5-LO resulted in a significant reduction of all the above-described parameters. In particular, we have observed a significant reduction of: (i) the degree of colon injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in staining (immunohistochemistry) for ICAM-1, VCAM-1, P-selectin, E-selectin caused by DNBS in the colon. Similarly, the treatment of 5-LOWT with zileuton (50 mg/kg per os twice a day) resulted in a significant reduction of all the above-described parameters. In addition, in in vitro study a significantly reduced chemotactic response to IL-8 was observed in peripheral blood leukocytes from 5-LOKO in comparison to 5-LOWT polymorphonuclear leukocyte. Similar results were obtained when we analyzed the chemotactic response of 5-LOWT cell incubated for 15 min with zileuton (50 microg/ml). Taken together, our results clearly demonstrate that 5-LO modulates neutrophil infiltration in experimental colitis through the expression of adhesion molecules.
Cuzzocrea
Salvatore
S
Department of Clinical and Experimental Medicine and Pharmacology, University of Messina Torre Biologica, Policlinico Universitario, Messina, Italy. salvator@unime.it
Rossi
Antonietta
A
Mazzon
Emanuela
E
Di Paola
Rosanna
R
Genovese
Tiziana
T
Muià
Carmelo
C
Caputi
Achille P
AP
Sautebin
Lidia
L
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D003967:Diarrhea / Q000235:genetics; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives; D005786:Gene Expression Regulation; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C045305:2,4-dinitrofluorobenzene sulfonic acid; D004139:Dinitrofluorobenzene; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase