IL-29 and IFNα differ in their ability to modulate IL-12 production by TLR-activated human macrophages and exhibit differential regulation of the IFNγ receptor expression

The interferon-lambda (IFN lambda) family of cytokines, consisting of interleukin-28A (IFN lambda 2), IL-28B (IFN lambda 3), and IL-29 (IFN lambda 1), have been extensively studied for their antiviral activities. However, little is known about the effect of IFN lambda on antigenpresenting cells. In the present study, we show for the first time that IL-29 can increase Toll-like receptor (TLR)-induced IL-12p40 production by human monocytederived macrophages. In contrast, IL-29 did not affect monocytes or monocytederived dendritic cells (DCs) because of restricted IL-28 receptor alpha chain expression by macrophages. Furthermore, IL29- treated macrophages were more responsive to IFN gamma, because IL-29 enhanced IFN gamma-induced IL-12p40 and tumor necrosis factor (TNF) production by macrophages on R848 stimulation. However, IFN alpha suppressed IFN gamma-induced IL-12p40 and tumor necrosis factor TNF production by human macrophages. The differential effects of IL-29 and IFN alpha on the responsiveness of macrophages to IFN gamma could not be explained by an effect on TLR7 or TLR8 mRNA expression or by altered IL-10 signaling. However, we demonstrated that IL-29 up-regulated, whereas IFN alpha down-regulated, the surface expression of the IFN gamma receptor 1 chain on macrophages, thereby resulting in differential responsiveness of TLR-challenged macrophages to IFN gamma. Our findings on the differences between IFN alpha and IL-29 in modulating TLR-induced cytokine production by macrophages may contribute to understanding the role of IFNs in regulating immunity to pathogens. (Blood. 2011;117(8):2385-2395)