title: Impaired inhibitory effect of interleukin-10 on the balance between matrix metalloproteinase-9 and its inhibitor in mononuclear cells from hyperhomocysteinemic subjects.
abstract: OBJECTIVE
  Homocysteine has been linked to increased risk of ischemic stroke and other cardiovascular events, but the mechanism by which elevated plasma levels of homocysteine promotes atherogenesis remains unclear. Matrix degradation, partly regulated by the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), plays an important role in atherogenesis and plaque destabilization, and we hypothesized an imbalance between MMPs and TIMPs in hyperhomocysteinemia.
  
  
  METHODS
  Serum MMP-9 and TIMP-1 was measured in 12 hyperhomocysteinemic and 12 control subjects. The release of MMP-9 and TIMP-1, with and without interleukin-10 (IL-10), and the effect of IL-10 on signal transducer and activator of transcription 3 (STAT3) phosphorylation were measured in peripheral blood mononuclear cells (PBMCs) from hyperhomocysteinemic and control subjects.
  
  
  RESULTS
  Our main findings were: (1) hyperhomocysteinemic subjects had raised serum levels of MMP-9 and MMP-9/TIMP-1 ratio comparing healthy controls; (2) although IL-10 markedly suppressed MMP-9 release from PBMCs in controls, no or only minor effect was seen in hyperhomocysteinemic subjects; (3) although IL-10 enhanced TIMP-1 levels in PBMCs from both hyperhomocysteinemic and control subjects, the increase was more prominent in controls, resulting in a marked difference in IL-10-induced changes in MMP-9/TIMP-1 ratio between these 2 groups; and (4) comparing PBMCs from controls, cells from hyperhomocysteinemic individuals had impaired IL-10-induced STAT3 phosphorylation.
  
  
  CONCLUSIONS
  Our findings suggest an attenuated inhibitory response to IL-10 on MMP-9 activity in hyperhomocysteinemic subjects, potentially promoting atherogenesis and plaque instability, representing a novel explanation for increased risk for atherosclerotic disease in these individuals.
authors.affiliation: Lipid Clinic, Rikshospitalet University Hospital, Oslo, Norway. kirsten.holven@medisin.uio.no
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Holven
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Vigdis
authors.initials: V
authors.lastname: Bjerkeli
authors.forename: Jan Kristian
authors.initials: JK
authors.lastname: Damås
authors.forename: Kjetil
authors.initials: K
authors.lastname: Retterstøl
authors.forename: Lars
authors.initials: L
authors.lastname: Mørkrid
authors.forename: Leiv
authors.initials: L
authors.lastname: Ose
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Marit S
authors.initials: MS
authors.lastname: Nenseter
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000453:epidemiology / Q000209:etiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood* / Q000150:complications / Q000201:enzymology; D016753:Interleukin-10 / Q000494:pharmacology / Q000502:physiology*; D053613:Janus Kinase 1; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053701:Receptors, Interleukin-10; D012306:Risk; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D020780:Matrix Metalloproteinase 9