Induction of Interleukin-6 by Hepatitis C Virus Core Protein in Hepatitis C–Associated Mixed Cryoglobulinemia and B-Cell Non–Hodgkin's Lymphoma

Abstract

Purpose: 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. Experimental Design: 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.

Hepatitis C virus core protein induces fibrogenic actions of hepatic stellate cells via toll-like receptor 2

“…In addition, LX-2 cells could be stimulated by a truncated core protein narrowing the critical sequence for TLR2 interactions to amino acids 1 and 115 of the HCV core protein in line with previous data. 30 The dimension of the effects seen in our experiments correspond well with previous works analyzing the induction of COL1A1, 28,36 MMP2 and TIMP1.…”

“…Denaturing HCV core protein by heat inactivation abolished its stimulating effect on LX-2 cells, suggesting a conformation-dependent interaction (Figure 2). LPS, a TLR4 ligand, 30 did not induce COL1A1 upregulation, thus excluding inadvertent activation of LX-2 cells by endotoxin contamination (Figure 2). …”

“…28 We and others have recently shown that HCV core protein triggers inflammatory cell activation by stimulating the pattern recognition receptor toll-like receptor 2 (TLR2). [29][30][31] After ligand binding, TLR2 recruits different signaling molecules that are also involved in the regulation of fibrosis. These include the adapter molecule MyD88, triggering interleukin-1 receptor-associated kinase activated by phosphorylation and leading to the recruitment of the mitogen activated kinase (MAPK) pathways jun-amino-terminal kinase (JNK), p38 and ERK1/2 that induce NFkB activation.…”

The toll‐like receptor 2 (TLR2) ‐196 to ‐174 del/ins polymorphism affects viral loads and susceptibility to hepatocellular carcinoma in chronic hepatitis C

“…6 Thus, our findings suggest divergent roles of TLR2 signaling in each of the two HCV-associated malignant diseases. Increased secretion of cytokines such as IL-6 following TLR2 stimulation is likely to act as growth factor for lymphoma development, whereas low level TLR2 expression and production of inflammatory cytokines associated with the TLR2 -196 to -174 del allele seems to allow for increased viral loads thus contributing to an increased risk to develop HCC.…”

“…4 TLR2 recognizes various bacterial components, and we and others have recently shown that TLR2 is triggered by HCV proteins core and NS3 leading to activation of inflammatory cells. 5,6 Moreover, transgenic mice expressing the HCV core protein have been shown to ultimately develop HCC. 7 The human TLR2 gene is located on chromosome 4q32.…”