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B and c-Jun N-Terminal Kinase and Enhances Chemokine Secretion on Activated Human Hepatic Stellate Cells1
Department of Medicine and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Activated hepatic stellate cells (HSCs) are the main producers of
extracellular matrix in the fibrotic liver and contribute to hepatic
inflammation through the secretion of chemokines and the recruitment of
leukocytes. This study assesses the function of CD40 on human HSCs.
Activated human HSCs express CD40 in culture and in fibrotic liver, as
determined by flow cytometry, RT-PCR, and immunohistochemistry. CD40
expression is strongly enhanced by IFN-
. Stimulation of CD40 with
CD40 ligand (CD40L)-transfected baby hamster kidney cells induces
NF-
B, as demonstrated by the activation of I-B kinase (IKK),
increased NF-B DNA binding, and p65 nuclear translocation.
CD40-activated IKK also phosphorylates a GST-p65 substrate at serine
536 in the transactivation domain 1. Concomitant with the activation of
IKK, CD40L-transfected baby hamster kidney cell treatment strongly
activates c-Jun N-terminal kinase. CD40 activation increases the
secretion of IL-8 and monocyte chemoattractant protein-1 by HSCs 10-
and 2-fold, respectively. Adenovirally delivered dominant negative (dn)
IKK2 and TNFR-associated factor 2dn inhibit IKK-mediated
GST-I-B and GST-p65 phosphorylation, NF-B binding, and IL-8
secretion, whereas IKK1dn and NF-B-inducing kinase dominant negative
do not have inhibitory effects. We conclude that the CD40-CD40L
receptor-ligand pair is involved in a cross-talk between HSCs and
immune effector cells that contributes to the perpetuation of HSC
activation in liver fibrosis through TNFR-associated factor 2- and
IKK2-dependent pathways.
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