We report here the identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state. Three closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3 (tentatively designated as IL-29, IL-28A and IL-28B, respectively, by HUGO). The expression of IFN-lambda mRNAs was inducible by viral infection in several cell lines. We identified a distinct receptor complex that is utilized by all three IFN-lambda proteins for signaling and is composed of two subunits, a receptor designated CRF2-12 (also designated as IFN-lambdaR1) and a second subunit, CRF2-4 (also known as IL-10R2). Both receptor chains are constitutively expressed on a wide variety of human cell lines and tissues and signal through the Jak-STAT (Janus kinases-signal transducers and activators of transcription) pathway. This receptor-ligand system may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.

SUMMARY Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.

This study explores the role of mevalonate inhibitors in the activation of NF-k ␤ and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNF-␣ , IL-1 ␤ , and IL-6) in rat primary astrocytes, microglia, and macrophages. Lovastatin and sodium phenylacetate (NaPA) were found to inhibit LPS-and cytokine-mediated production of NO and expression of iNOS in rat primary astrocytes; this inhibition was not due to depletion of end products of mevalonate pathway (e.g., cholesterol and ubiquinone). Reversal of the inhibitory effect of lovastatin on LPS-induced iNOS expression by mevalonate and farnesyl pyrophosphate and reversal of the inhibitory effect of NaPA on LPS-induced iNOS expression by farnesyl pyrophosphate, however, suggests a role of farnesylation in the LPS-mediated induction of iNOS. The inhibition of LPS-mediated induction of iNOS by FPT inhibitor II, an inhibitor of Ras farnesyl protein transferase, suggests that farnesylation of p21 ras or other proteins regulates the induction of iNOS. Inhibition of LPSmediated activation of NF-k ␤ by lovastatin, NaPA, and FPT inhibitor II in astrocytes indicates that the observed inhibition of iNOS expression is mediated via inhibition of NF-k ␤ activation. In addition to iNOS, lovastatin and NaPA also inhibited LPS-induced expression of TNF-␣ , IL-1 ␤ , and IL-6 in rat primary astrocytes, microglia, and macrophages. This study delineates a novel role of the mevalonate pathway in controlling the expression of iNOS and different cytokines in rat astrocytes, microglia, and macrophages that may be important in developing therapeutics against cytokineand NO-mediated neurodegenerative diseases. ( J. Clin. Invest. 1997. 100:2671-2679.)

Recently discovered type III IFNs (IFN-L) exert their antiviral and immunomodulatory activities through a unique receptor complex composed of IFN-LR1 and interleukin-10 receptor 2. To further study type III IFNs, we cloned and characterized mouse IFN-L ligand-receptor system. We showed that, similar to their human orthologues, mIFN-L2 and mIFN-L3 signal through the IFN-L receptor complex, activate IFN stimulated gene factor 3, and are capable of inducing antiviral protection and MHC class I antigen expression in several cell types including B16 melanoma cells. We then used the murine B16 melanoma model to investigate the potential antitumor activities of IFN-Ls. We developed B16 cells constitutively expressing murine IFN-L2 (B16.IFN-L2 cells) and evaluated their tumorigenicity in syngeneic C57BL/6 mice. Although constitutive expression of mIFN-L2 in melanoma cells did not affect their proliferation in vitro, the growth of B16.IFN-L2 cells, when injected s.c. into mice, was either retarded or completely prevented. We found that rejection of the modified tumor cells correlated with their level of IFN-L2 expression. We then developed IFN-L-resistant B16.IFN-L2 cells (B16.IFNL2Res cells) and showed that their tumorigenicity was also highly impaired or completely abolished similar to B16.IFN-L2 cells, suggesting that IFN-Ls engage host mechanisms to inhibit melanoma growth. These in vivo experiments show the antitumor activities of IFN-Ls and suggest their strong therapeutic potential. (Cancer Res 2006; 66(8): 4468-77)