Role of matrix metalloproteinases, proinflammatory cytokines, and oxidative stress-derived molecules in hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy.
OBJECTIVE
Mixed cryoglobulinemia (MC) is a systemic vasculitis, usually associated with hepatitis C virus (HCV) infection. The molecular mechanisms responsible for HCV-associated MC (HCV-MC) vasculitis are largely unknown. This study was undertaken to assess the expression profile of selected genes involved in inflammatory vascular damage in patients with HCV-MC vasculitis, patients with polyarteritis nodosa (PAN), and patients with noninflammatory idiopathic neuropathy.


METHODS
The quantitative expression levels of 42 selected genes involved in inflammatory vascular damage were assessed in nerve lesions of patients with HCV-MC vasculitis, PAN (rheumatic disease controls), and noninflammatory idiopathic neuropathy (noninflammatory neuropathy controls), using real-time reverse transcriptase-polymerase chain reaction. Genes were considered to be differentially expressed when there was a >2-fold difference in mean expression levels between groups and the P value was less than 0.05.


RESULTS
Expression levels of 8 genes were significantly increased in HCV-MC patients versus control patients with noninflammatory idiopathic neuropathy, with the highest increase for metallothionein 1 H (MT1H), a hypoxic and oxidative stress protein. Compared with PAN patients, HCV-MC patients had higher expression levels of genes encoding oxidative stress-derived molecules (MT1H, endothelial cell nitric oxide synthase 3, Hsp70, and Hsp90) and tissue plasminogen activator and lower expression levels of matrix metalloproteinase 7 (MMP-7). HCV-MC neuropathies were classified according to their morphologic pattern and the presence or absence of necrotizing arteritis. MMP-1, MMP-7, MMP-9, and interleukin-1beta were up-regulated in patients with necrotizing arteritis.


CONCLUSIONS
This comprehensive molecular study of HCV-MC vasculitis provides strong evidence that MMPs, proinflammatory cytokines, and oxidative stress-derived molecules have a role in the pathogenesis of HCV-MC vasculitis neuropathy.
Saadoun
David
D
Université Pierre et Marie Curie-Paris VI, CNRS UMR 7087, and Hôpital Pitié-Salpétrière, Paris, France.
Bieche
Ivan
I
Authier
François-Jérome
FJ
Laurendeau
Ingrid
I
Jambou
Florence
F
Piette
Jean Charles
JC
Vidaud
Michel
M
Maisonobe
Thierry
T
Cacoub
Patrice
P
D000328:Adult; D000368:Aged; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D003449:Cryoglobulinemia / Q000378:metabolism / Q000821:virology*; D005260:Female; D020869:Gene Expression Profiling; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D045726:Metalloproteases / Q000235:genetics* / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010543:Peroneal Nerve / Q000378:metabolism / Q000473:pathology; D010488:Polyarteritis Nodosa / Q000378:metabolism / Q000473:pathology / Q000821:virology; D011115:Polyneuropathies / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D018925:Chemokines; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008668:Metallothionein; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D045726:Metalloproteases; D010959:Tissue Plasminogen Activator