Linked Life Data

11566448

Source:http://linkedlifedata.com/resource/pubmed/id/11566448

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2001-9-21
pubmed:abstractText
5-Aminosalicylate, which is considered to be the active moiety of sulfasalazine, is one of the most widely used agents for treatment of inflammatory bowel disease. However, its mechanism of action is unclear. In this report, we provide evidence that the phospholipase D pathway is a target for this drug in macrophages. Activation of phospholipase D leads to the generation of important second messengers such as phosphatidic acid, lysophosphatidic acid and diacylglycerol, all of which can regulate cellular responses involved in inflammation. Murine peritoneal macrophages were labeled with [(3)H]myristate, incubated with various drugs, agonists, or inhibitors, and phospholipase D activity was assayed. 5-Aminosalicylate or sulfasalazine stimulated phospholipase D in a time- and concentration-dependent manner. Chelation of extracellular Ca(2+) inhibited phospholipase D activation by either of these drugs whereas pretreatment of macrophages with the tyrosine kinase inhibitor genistein had no effect. Downregulation of protein kinase C by prolonged incubation with phorbol ester completely blocked the activation of phospholipase D. Pertussis toxin decreased the activation of phospholipase D. The levels of inositol 1,4,5-trisphosphate increased by 260% after treatment of macrophages with 5-aminosalicylate. A phosphoinositide-specific phospholipase C inhibitor U73122 blocked phospholipase D activation completely. Interestingly, long-term preincubation of the macrophages with a relatively low concentration of 5-aminosalicylate that did not stimulate phospholipase D activity by itself, potentiated the effect of phorbol ester-induced activation of phospholipase D. Taken together, these results show that 5-aminosalicylate activates phospholipase D via a pathway involving inositol 1,4,5-trisphosphate generation, calcium fluxes, and Gi/Go. Although the mechanisms by which phospholipase D activation by 5-aminosalicylate or sulfasalazine might attenuate inflammatory responses in the intestine remain to be defined, these results highlight a novel potential mechanism of action for these drugs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0006-3002
pubmed:author
pubmed:issnType
Print
pubmed:day
28
pubmed:volume
1533
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
110-8
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:11566448-Animals, pubmed-meshheading:11566448-Anti-Inflammatory Agents, Non-Steroidal, pubmed-meshheading:11566448-Calcium, pubmed-meshheading:11566448-Cells, Cultured, pubmed-meshheading:11566448-Ceramides, pubmed-meshheading:11566448-Dose-Response Relationship, Drug, pubmed-meshheading:11566448-Enzyme Activation, pubmed-meshheading:11566448-Female, pubmed-meshheading:11566448-Macrophages, Peritoneal, pubmed-meshheading:11566448-Mesalamine, pubmed-meshheading:11566448-Mice, pubmed-meshheading:11566448-Models, Chemical, pubmed-meshheading:11566448-Phospholipase D, pubmed-meshheading:11566448-Protein Kinase C, pubmed-meshheading:11566448-Signal Transduction, pubmed-meshheading:11566448-Sphingomyelins, pubmed-meshheading:11566448-Sulfasalazine, pubmed-meshheading:11566448-Time Factors, pubmed-meshheading:11566448-Tritium
pubmed:year
2001
pubmed:articleTitle
5-Aminosalicylate stimulates phospholipase D activity in macrophages.
pubmed:affiliation
Division of Gastroenterology, Department of Medicine, University of British Columbia, 100-2647 Willow St., V5Z 3P1, Vancouver, BC, Canada.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't