Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection.
Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the host's immunomodulatory response to infective agents. To evaluate the TNF-alpha system in patients with chronic hepatitis C virus (HCV) infection, plasma, serum, and peripheral blood mononuclear cells (PBMC) were prospectively collected from 53 patients and 33 healthy control subjects. Circulating TNF-alpha and TNF receptors were assayed by their respective enzyme immunoassays. In addition, TNF-alpha mRNA was quantitated in PBMC using a branched DNA assay, and production of TNF-alpha by PBMC with and without lipopolysaccharide was also assessed. Patients with chronic HCV infection had a higher level of circulating TNF-alpha compared to healthy control subjects (9.62 +/- 6.01 vs 3.66 +/- 1.23 pg/ml, P < 0.001). They also had higher circulating levels of TNF receptors compared to control (CD120a: 3323 +/- 1267, pg/ml, N = 49 vs 1855 +/- 422 pg/ml, N = 33, P < 0.001; CD120b: 1290 +/- 650 pg/ml, N = 51, vs 863 +/- 207 pg/ml, N = 33, P < 0.001). Plasma TNF-alpha level correlated with circulating CD120a (r = 0.52, N = 49, P < 0.001) and weakly with CD120b (r = 0.32, N = 51, P = 0.02). Plasma TNF-alpha also correlated with markers of hepatocellular injury, including ALT (r = 0.34, N = 53, P = 0.01) and alpha-GST (r = 0.31, N = 43, P = 0.042), but not with serum HCV RNA levels. There was no difference in the TNF-alpha mRNA levels in PBMC between patients with chronic HCV infection (1.4 +/- 1.9 units/10[6] cells, N = 8) and healthy control subjects (2.1 +/- 1.4 units/10[6] cells, N = 8, P = NS). There was also no difference in the spontaneous production of TNF-alpha by PBMC (1 x 10[6] cells/ml) between patients with chronic HCV infection (14.2 +/- 36.5 pg/ml, N = 11) and healthy subjects (11.9 +/- 14.0 pg/ml, N = 14, P = NS). However, patients with chronic HCV infection produced more TNF-alpha upon stimulation with lipopolysaccharide compared to healthy control subjects (1278 +/- 693 pg/ml, N = 11, vs 629 +/- 689 pg/ml, N = 14, P < 0.05). These data indicate that the TNF-alpha system is activated in patients with chronic HCV infection.
Nelson
D R
DR
Department of Medicine, University of Florida, Gainesville, USA.
Lim
H L
HL
Marousis
C G
CG
Fang
J W
JW
Davis
G L
GL
Shen
L
L
Urdea
M S
MS
Kolberg
J A
JA
Lau
J Y
JY
D000293:Adolescent; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
D012333:RNA, Messenger; D012367:RNA, Viral; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000410:Alanine Transaminase