IFN-lambda is able to augment TLR-mediated activation and subsequent function of primary human B cells

During the past decade, increased emphasis has been placed on finding alternatives to IFN-alpha-based therapies. One such alternative, IFN-lambda, has shown therapeutic promise in a variety of diseases, but research of this family of cytokines has been primarily focused on their antiviral activities. The goal of the present study was to investigate the role of IFN-lambda in the regulation and modulation of B cell function. We show that, similar to IFN-alpha, IFN-lambda 1 is able to augment TLR-mediated B cell activation, partially attributed to an upregulation of TLR7 expression, and that both naive and memory B cells express the limiting type III IFN receptor component, IFN-lambda R1. Furthermore, this IFN-lambda-enhanced B cell activation resulted in increased cytokine and Ig production during TLR7 challenge, most prominently after the addition of helper T cell signals. Ultimately, these elevated cytokine and Ig levels could be partially attributed to the increase in proliferation of TLR7-challenged B cells by both type I and type III IFNs. These findings demonstrate the ability of IFN-lambda to boost humoral immunity, an important attribute to consider for further studies on immunity to pathogens, vaccine development, and ongoing advancement of therapeutic strategies aimed at replacing IFN-alpha-based treatments with IFN-lambda

Role for IL-10 in inducing functional impairment of monocytes upon TLR4 ligation in patients with chronic HCV infections

The consequences of chronic infection with the HCV on immunity to distinct pathogens are not fully appreciated, despite the potent modulatory effects of HCV on the immune system. We observed that upon TLR4 ligation, monocytes from chronic HCV patients demonstrated three to five times lower TNF and IL-12p40 production as compared with healthy individuals. However, augmented production of TNF, IL-12p40, and IL-12p70 by monocytes was observed upon stimulation with R848. Importantly, we observed that the levels of IL-10 in chronic HCV patients are higher in serum and that more IL-10 is produced by monocytes as compared with healthy individuals. The inhibitory effect of IL-10 on the production of proinflammatory cytokines by monocytes was only observed upon LPS stimulation but not upon R848 stimulation, showing that only the TLR4 pathway in monocytes is sensitive to the suppressive effects of IL-10. Interestingly, monocytes stimulated with the TLR4 agonist, but not TLR8 agonist, produced higher levels of IL-10 when exposed to patient serum as compared with serum from healthy individuals. Our results indicate that by differentially affecting TLR4 and TLR8 pathways, IL-10 may mediate highly selective modulation of the function of monocytes observed in chronic HCV patients. This suggests that there is no overall increased susceptibility to pathogens but a specific suppression of the functionality of TLR4 signaling pathway in monocytes, which is, at least partly, mediated via IL-10. J. Leukoc. Biol. 89: 981-988; 2011