Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV.

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.

Plasmacytoid dendritic cells initiate a complex chemokine and cytokine network and are a viable drug target in chronic HCV patients.

Plasmacytoid dendritic cells (pDCs) are the professional type I interferon (IFN)-producing cells, and upon activation they traffic to lymph organs, where they bridge innate and adaptive immunity. Using multianalyte profiling (MAP), we have mapped the key chemokines and cytokines produced in response to pDC activation, taking into consideration the role of autocrine IFN, as well as paracrine effects on other innate cells (e.g., monocytes and conventional DCs). Interestingly, we identify four distinct cytokine/chemokine loops initiated by Toll-like receptor engagement. Finally, we applied this analytic approach to the study of pDC activity in chronic hepatitis C patients. Based on the activation state of pDCs in fresh blood, the lack of agonistic activity of infectious virions, the production of a broad array of cytokines/chemokines once stimulated, and the direct effects of pDCs on other PBMCs, we conclude that the pDCs from hepatitis C virus (HCV)-infected individuals are fully functional and are, indeed, a viable drug target. In sum, this study provides insight into the use of MAP technology for characterizing cytokine networks, and highlights how a rare cell type integrates the activation of other inflammatory cells. Furthermore, this work will help evaluate the therapeutic application of pDC agonists in diseases such as chronic HCV infection.

Cyclic AMP-phosphodiesterases inhibitor improves sodium excretion in rats with cirrhosis and ascites.

BACKGROUND: The mechanisms responsible for renal dysfunction and sodium retention in cirrhosis remain unclear. Cyclic AMP (cAMP) regulates sodium reabsorption in the proximal nephron. This study investigates the role of cAMP metabolism in renal dysfunction in cirrhosis. METHODS: Renal function was studied by the clearance technique in anesthetized control and cirrhotic rats with or without ascites. cAMP phosphodiesterase (PDE) activity was measured in the renal cortex in vitro. Moroever, the effects on renal function of the intravenous administration of cAMP and rolipram, a powerful and specific cAMP-PDE4 inhibitor, were evaluated. RESULTS: In control and in non-ascitic cirrhotic rats, cAMP administration significantly increased sodium and phosphate excretions, but did not change these excretions in cirrhotic rats with ascites. cAMP-PDE activity was higher in ascitic than in control rats (P < 0.05). Rolipram infusion significantly increased sodium and phosphate excretion only in cirrhotic rats with ascites. CONCLUSION: These results suggest that increased renal cAMP-PDE activity is responsible for resistance to the natriuretic effects of cAMP in cirrhosis and plays a role in the development of ascites.

Extracellular cAMP inhibits proximal reabsorption: are plasma membrane cAMP receptors involved?

Glucagon binding to hepatocytes has been known for a long time to not only stimulate intracellular cAMP accumulation but also, intriguingly, induce a significant release of liver-borne cAMP in the blood. Recent experiments have shown that the well-documented but ill-understood natriuretic and phosphaturic actions of glucagon are actually mediated by this extracellular cAMP, which inhibits the reabsorption of sodium and phosphate in the renal proximal tubule. The existence of this "pancreato-hepatorenal cascade" indicates that proximal tubular reabsorption is permanently influenced by extracellular cAMP, the concentration of which is most probably largely dependent on the insulin-to-glucagon ratio. The possibility that renal cAMP receptors may be involved in this process is supported by the fact that cAMP has been shown to bind to brush-border membrane vesicles. In other cell types (i.e., adipocytes, erythrocytes, glial cells, cardiomyocytes), cAMP eggress and/or cAMP binding have also been shown to occur, suggesting additional paracrine effects of this nucleotide. Although not yet identified in mammals, cAMP receptors (cARs) are already well characterized in lower eukaryotes. The amoeba Dictyostelium discoideum expresses four different cARs during its development into a multicellular organism. cARs belong to the superfamily of seven transmembrane domain G protein-coupled receptors and exhibit a modest homology with the secretin receptor family (which includes PTH receptors). However, the existence of specific cAMP receptors in mammals remains to be demonstrated. Disturbances in the pancreato-hepatorenal cascade provide an adequate pathophysiological understanding of several unexplained observations, including the association of hyperinsulinemia and hypertension, the hepatorenal syndrome, and the hyperfiltration of diabetes mellitus. The observations reviewed in this paper show that cAMP should no longer be regarded only as an intracellular second messenger but also as a first messenger responsible for coordinated hepatorenal functions, and possibly for paracrine regulations in several other tissues.