Induction of interleukin-6 by hepatitis C virus core protein in hepatitis C-associated mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma.
OBJECTIVE
Chronic hepatitis C carries the risk to develop mixed cryoglobulinemia (MC) and B-cell non-Hodgkin's lymphoma (B-NHL), possibly because viral antigens stimulate the host's inflammatory response via extracellular pattern recognition receptors (PRR). To clarify this issue, we studied whether recognition of hepatitis C virus (HCV) proteins by PRR is involved in the pathogenesis of HCV-associated MC or B-NHL.


METHODS
Peripheral blood mononuclear cells of patients with HCV-associated B-NHL (n = 12), MC (n = 14), uncomplicated hepatitis C (n = 12), and healthy volunteers (n = 12) were incubated with the recombinant HCV proteins E2, core, and NS3 to study induction of cytokine production, stimulation of B-cell proliferation, and immunoglobulin secretion. In addition, serum levels of interleukin-6 (IL-6) were measured by ELISA.


RESULTS
HCV core was the only studied protein, which induced production of IL-6 and IL-8 in CD14(+) cells. IL-6 induction was mediated via Toll-like receptor 2 (TLR2) and lead to increased B-cell proliferation in vitro. TLR2 expression on monocytes and IL-6 serum concentrations were increased in all groups of HCV-infected patients compared with healthy controls and were highest in MC (P < 0.05).


CONCLUSIONS
Increased secretion of IL-6 via stimulation of TLR2 by HCV core protein may play a role in the pathogenesis of hepatitis C-associated MC and B-NHL.
Feldmann
Georg
G
Department of Internal Medicine 1, University of Bonn, Bonn, Germany. gfeldma4@jhmi.edu
Nischalke
Hans Dieter
HD
Nattermann
Jacob
J
Banas
Brigitte
B
Berg
Thomas
T
Teschendorf
Christian
C
Schmiegel
Wolff
W
Dührsen
Ulrich
U
Halangk
Juliane
J
Iwan
Agathe
A
Sauerbruch
Tilman
T
Caselmann
Wolfgang H
WH
Spengler
Ulrich
U
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D003449:Cryoglobulinemia / Q000097:blood / Q000209:etiology*; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000097:blood / Q000150:complications* / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood; D016209:Interleukin-8 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000097:blood / Q000209:etiology*; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000097:blood / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000276:immunology*
D015850:Interleukin-6; D016209:Interleukin-8; D011994:Recombinant Proteins; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014758:Viral Core Proteins