The effect of obesity on intrahepatic cytokine and chemokine expression in chronic hepatitis C infection.
BACKGROUND
Obese subjects with chronic hepatitis C virus (HCV) infection have more rapidly progressive liver disease. Objective In this study, we aimed to compare the hepatic cytokine and chemokine profiles in obese and lean subjects with chronic HCV infection using qRT-PCR and immunohistochemistry.


METHODS
Liver biopsies from 55 subjects were studied, including 20 with chronic hepatitis C, 25 with non-alcoholic fatty liver disease and 10 subjects with non-diseased liver.


RESULTS
Compared to the control groups, the liver injury in chronic hepatitis C was characterised by increased expression of several T-helper-1 cytokines including interferon-gamma and tumour necrosis factor-alpha, and chemokines such as RANTES, IP-10 and MCP-1. In particular, in comparison with lean (BMI <or=25 kg/m(2)) HCV infected subjects, obese (BMI>or=30 kg/m(2)) HCV infected subjects had increased hepatic expression of interferon-gamma (p=0.004) and tumour necrosis factor-alpha (p<0.001), as well as increased expression of IP-10 (p=0.009) and MCP-1 (p<0.001). Localisation of these inflammatory chemokines revealed that in comparison to lean-HCV subjects, HCV infected liver from obese subjects exhibited significantly increased expression of IP-10 (p<0.001) and MCP-1 (p=0.02) in the inflammatory infiltrate of the portal tracts. In parallel, there was increased CD3 infiltration in the liver of obese-HCV subjects.


CONCLUSIONS
The data provide important mechanistic information on the cause of hepatic injury in obese-HCV subjects including: (1) enhanced T helper-1 cytokine response patterns-to promote hepatocellular injury; (2) increased expression of the chemokines IP-10 and MCP-1 at both the mRNA and protein levels-to enhance inflammatory cell recruitment; (3) differing localisation of these chemokines within the liver of obese-HCV versus lean-HCV subjects-implying different inducing stimuli and; (4) increased CD3 expression in the liver of obese-HCV subjects-concordant with the increased expression of T cell chemoattractants.
Palmer
Clovis
C
Centre for Infection and Inflammation Research, School of Medical Sciences, Sydney, Australia.
Corpuz
Theresa
T
Guirguis
Marianne
M
O'Toole
Sandra
S
Yan
Kenneth
K
Bu
Yagmin
Y
Jorgenson
John
J
Talbot
Michael
M
Loi
Kenneth
K
Lloyd
Andrew
A
Zekry
Amany
A
D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005234:Fatty Liver / Q000276:immunology; D005260:Female; D015870:Gene Expression; D019698:Hepatitis C, Chronic / Q000150:complications / Q000276:immunology*; D006801:Humans; D008099:Liver / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018417:Th1 Cells / Q000276:immunology
D017252:CD3 Complex; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger