Linked Life Data

16476765

Source:http://linkedlifedata.com/resource/pubmed/id/16476765

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2006-2-22
pubmed:abstractText
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal-regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-10399150, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-10430507, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-10502407, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-10821323, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-10847765, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-11385505, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-11500833, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-11696591, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-11728335, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-11751396, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-11788600, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-11908910, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12163444, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12422218, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12538717, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12576552, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12594266, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12626426, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12629065, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12670400, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-12932358, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-14707106, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15007111, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15136515, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15145635, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15157852, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15173058, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15207950, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15229351, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15677697, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15699169, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-15878848, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-1967820, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-7530361, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-7585182, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-7948424, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-8199197, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-8419946, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-8811180, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-8934546, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-8977253, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-9300784, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-9510155, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-96199, http://linkedlifedata.com/resource/pubmed/commentcorrection/16476765-9647670
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-1007
pubmed:author
pubmed:issnType
Print
pubmed:day
20
pubmed:volume
203
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
401-12
pubmed:dateRevised
2011-11-4
pubmed:meshHeading
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