Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV
Armanda Casrouge, … , Stanislas Pol, Matthew L. Albert
Armanda Casrouge, … , Stanislas Pol, Matthew L. Albert
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):308-317. https://doi.org/10.1172/JCI40594.
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Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV

Abstract

Chronic infection with hepatitis C virus (HCV) is a major public health problem, with nearly 170 million infected individuals worldwide. Current treatment for chronic infection is a combination of pegylated IFN-α2 and ribavirin (RBV); however, this treatment is effective in fewer than 50% of patients infected with HCV genotype 1 or 4. Recent studies identified the chemokine CXCL10 (also known as IP-10) as an important negative prognostic biomarker. Given that CXCL10 mediates chemoattraction of activated lymphocytes, it is counterintuitive that this chemokine correlates with therapeutic nonresponsiveness. Herein, we offer new insight into this paradox and provide evidence that CXCL10 in the plasma of patients chronically infected with HCV exists in an antagonist form, due to in situ amino-terminal truncation of the protein. We further demonstrated that dipeptidyl peptidase IV (DPP4; also known as CD26), possibly in combination with other proteases, mediates the generation of the antagonist form(s) of CXCL10. These data offer what we believe to be the first evidence for CXCL10 antagonism in human disease and identify a possible factor contributing to the inability of patients to clear HCV.

Authors

Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol, Matthew L. Albert

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Figure 5

Elevated X-prolyl DPP activity in chronic HCV patients is mediated by DPP4.

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Elevated X-prolyl DPP activity in chronic HCV patients is mediated by DP...
(A) The activity of DPP4 was measured using a luciferase-based assay. Plasma from chronic NRs (n = 10), SVRs (n = 8), and healthy donors (n = 8) were tested in the presence or absence of the pan-DPP inhibitor IPI and the DPP4-specific inhibitor sitagliptin. The ratio of RLU of sample/RLU of PBS is represented, with each dot being the average of replicate wells for a single individual. This experiment is representative of 2 independent assays. (B) For in vitro experiments, human recombinant CXCL10 (1–77 aa) was digested in vitro with recombinant DPP4 to obtain CXCL10 (3–77 aa). In migration studies, human PHA-T blasts were prepared as described in Methods. Each bar is the mean of duplicate wells, and error bars indicate 1 SD of the mean. This experiment is representative of results obtained with 3 different healthy donors. (C) CHO-K1 cells were stably transfected with a plasmid expressing human CXCR3. Fura-3–AM fluorescent dye–labeled CXCR3-expressing CHO cells were used for Ca2+ flux experiments. Arrows indicate the injection of the stimulant. In the first plot, 1 μM CXCL10 (1–77 aa) was used. In the second plot, 1 μM CXCL10 (3–77 aa) was used. And in the third plot, cells were incubated at room temperature for 5 minutes with 1 μM CXCL10 (3–77 aa) (pre-tx), followed by a stimulation with 0.2 μM CXCL10 (1–77 aa). Data are representative of 3 independent experiments.