Visvanathan, K.; Skinner, N.; Kurtovic, J.; Nagree, A.; McIver, C.J.; Williams, R.; Riordan, S.M.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA35
Academic Journal
Background: Innate immunity to microbial pathogens, leading to the production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α, occurs as a result of activation of toll-like receptors (TLRs). Expression of TLRs has not been investigated in chronic hepatitis C (CHC). This is important as TNF-α may contribute to liver damage in this disorder. Methods: We studied 16 hepatitis C virus RNA-positive patients (genotype 1, n = 11; 2, n = 2; 3, n = 3) with CHC (median Ishak histological activity score 4, range 2-7; median stage 2, range 1-4) and raised serum ALT levels (median 109, range 55-350 U/L; normal 15-45 U/L) and 32 healthy controls. TLR2 and TLR4 expression on CD14+ve peripheral blood mononuclear cells (PBMCs) was measured by flow cytometry. Serum TNF-α levels were measured by ELISA (R&D Systems, USA). Results: TLR2 expression on PBMCs (expressed as a ratio to results in controls) was significantly increased in patients with CHC (median 1.18, range 0.77-2.41, p = 0.001). TLR4 expression was also significantly increased in this group (median 1.25, range 0.94-1.66, p < 0.0005). Serum TNF-α levels were significantly higher in CHC patients (median 2.3, range 0.8-9.3 pg/mL) than controls (median 1.9, range 0.8-3.4 pg/mL) and were correlated significantly with PBMC expression of TLR2 (r = 0.58, p < 0.0005) but not TLR4 (r = 0.01, p = 0.96). In CHC patients, serum ALT levels were correlated significantly with TLR2 expression (r = 0.74, p = 0.001) and TNF-α levels (r = 0.53, p = 0.05). Conclusions: Up regulation of PBMC expression of TLR2 and TLR4 occurs in CHC. Cell signalling via TLR2, in particular, may contribute to both increased circulating TNF-α levels and liver damage in this disorder. These findings provide novel insight into the pathogenesis of CHC.


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