Elevated circulating levels of
chemokines have been reported in patients with
dengue fever and are proposed to contribute to the pathogenesis of
dengue disease. To establish in vitro models for
chemokine induction by
dengue 2 virus (DEN2V), we studied a variety of human cell lines and primary cells. DEN2V
infection of HepG2 and primary dendritic cells induced the production of
interleukin-8 (IL-8),
RANTES,
MIP-1alpha, and
MIP-1beta, whereas only
IL-8 and
RANTES were induced following dengue virus
infection of HEK293 cells.
Chemokine secretion was accompanied by an increase in steady-state
mRNA levels. No
chemokine induction was observed in HEK293 cells treated with
poly(I:C) or
alpha interferon, suggesting a direct effect of
virus infection. To determine the mechanism(s) involved in the induction of
chemokine production by DEN2V, individual dengue virus genes were cloned into plasmids and expressed in HEK293 cells. Transfection of a plasmid expressing NS5 or a dengue virus replicon induced
IL-8 gene expression and secretion.
RANTES expression was not induced under these conditions, however. Reporter assays showed that
IL-8 induction by NS5 was principally through
CAAT/enhancer binding protein, whereas DEN2V
infection also induced
NF-kappaB. These results indicate a role for the
dengue virus NS5 protein in the induction of
IL-8 by DEN2V
infection. Recruitment and activation of potential target cells to sites of DEN2V replication by virus-induced
chemokine production may contribute to viral replication as well as to the inflammatory components of dengue virus disease.