title: HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts.
abstract: Proinflammatory cytokines and eicosanoids are central players in intestinal inflammation. IL-1, a key cytokine associated with intestinal mucosal inflammation, induces COX-2 expression in human colonic myofibroblasts (CMF) and increased prostaglandin E(2) secretion is associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). We have previously demonstrated that IL-1alpha-induced cyclooxygenase-2 (COX-2) expression is the result of NF-kappaB- and ERK-mediated transcription, as well as COX-2 message stabilization, which depends on p38, MAPKAPK-2 (MK-2) and human antigen R (HuR) RNA binding protein activation. Lipoxygenase (LOX)-derived hydroxyeicosatetraenoic acids (HETEs) are elevated in IBD and colonic adenomas and "cross talk" has been observed between the COX and LOX pathways. Since COX-2 expression is primarily in CMFs in colonic adenomas, we examined the impact of LOX metabolites, particularly HETEs, on IL-1alpha-induced COX-2 expression in human CMFs. Although 5(S)-, 12(R)-, and 15(S)-HETEs alone had little to no effect on COX-2 expression, they enhanced IL-1-mediated COX-2 expression 3.6 +/- 0.5-fold. Studies utilizing heterogeneous nuclear RNA amplification and 5,6-dichloro-beta-d-ribofuranosylbenzimidazole treatment were undertaken to measure COX-2 transcription and message stabilization, respectively. We found that HETEs enhanced IL-1-induced COX-2 mRNA levels in CMF as the result of increased p38, MK-2, and HuR activity, increasing message stability greater than that observed with IL-1 alone. Thus HETEs can act synergistically with IL-1alpha to induce COX-2 expression in human CMFs. HETEs may play a role in both colonic inflammation and in increasing the risk of CRC in IBD independently and via induction of COX-2-mediated prostaglandin secretion.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA. jdimari@utmb.edu
authors.forename: J F
authors.initials: JF
authors.lastname: Di Mari
authors.forename: J I
authors.initials: JI
authors.lastname: Saada
authors.forename: R C
authors.initials: RC
authors.lastname: Mifflin
authors.forename: J D
authors.initials: JD
authors.lastname: Valentich
authors.forename: D W
authors.initials: DW
authors.lastname: Powell
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002478:Cells, Cultured; D003106:Colon; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D053582:Interleukin-1alpha / Q000502:physiology*; D007413:Intestinal Mucosa; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000954:Antigens, Surface; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D006893:Hydroxyeicosatetraenoic Acids; D053582:Interleukin-1alpha; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C098770:ELAVL1 protein, human