Expression of IP-10 chemokine is regulated by pro-inflammatory cytokines in cultured hepatocytes

ABSTRACT

Chemokines are classified in four distinct groups as CXC, CC, CX3C and C, depending on the presence or absence of a motif called ELR [Arg-Leu-Glu] before the first cysteine residue in their structure. CXC chemokines are also subdivided into ELR+and ELR-. Increasing evidence has indicated the existence of a chemokine network in the liver which is involved in both physiological responses and, under certain circumstances, pathological and repair processes following hepatic injury. The CXC chemokines play a major role in both these processes, and much attention has been focused on their therapeutic applications to liver disease. The aim of this study was to examine the response of cultured hepatocytes to exogenous inflammatory cytokines [TNF-alpha and IFN-gamma] regarding expression of IP-10 and growth regulatory oncogen [Gro] chemokines. In this study we employed western and northern analysis to measure chemokines at the level of protein and mRNA by hepatocytes in response to pro-inflammatory cytokines. We found that, the pro-inflammatory cytokines, TNF-alpha and IFN-gamma, selectively stimulated expression of IP-10 but were without effect on Gro. This confirms a potential direct involvement of these cytokines in chemokine production by hepatocytes. Thus, IFN-gamma and TNF-alpha may play a role in hepatic injury and inflammation and produce some of their biological effects by localized induction of chemokines by hepatocytes. Given the similarity to an acute phase response, we were able to show that IFN-gamma and TNF-alpha mimicked the effects of cell isolation and culture on induction of IP-10 expression. Further, evidence for linkages between IFN-gamma and TNF-alpha and liver injuries is seen in hepatitis C and hepatitis B in which increased levels of TNF-alpha and its soluble receptor were reported