IFN-λ Research Articles

IL-28B genetic variation, gender, age, jaundice, hepatitis C virus genotype, and hepatitis B virus and HIV co-infection in spontaneous clearance of hepatitis C virus.

Spontaneous viral clearance observed in some patients is one of the variants of the hepatitis C virus (HCV) infection natural history. We aimed to look at the complexity of factors affecting the spontaneous clearance of HCV (SC HCV). A total of 357 anti-HCV positive patients (309 with chronic hepatitis C and 48 patients with SC HCV) were included into the study. We studied the effects of the interleukin-28B (IL-28B) gene polymorphism, gender, age, the routes of virus transmission, past hepatitis C with jaundice, HCV genotype, and hepatitis B virus (HBV) and HIV co-infection on the outcome of HCV infection. Based on the study results, the SC HCV was found in 48 individuals (13.4%). The most significant positive factors affecting the SC HCV included IL-28B single nucleotide polymorphism (SNP) rs12979860 (CC) and SNP rs8099917 (TT) (OR 4.03, p<0.001) and (OR 3.14, p<0.002), female gender (OR 2.72, p<0.001), young age (OR 2.30, p<0.008), and past history of jaundice (OR 5.12, p<0.001). The markers of a past HBV infection were found significantly more often in SC. Positive predictors of the SC HCV include favorable IL-28B genotype, female gender, young age, a history of jaundice, markers of a past HBV infection, the absence of HIV infection, but not the viral genotype.

The unfolded protein response contributes to antiproliferative and proapoptotic effects of IFN-λ4 in human hepatic cells

Abstract IFN-λ4 is a type-III interferon with strong clinical significance in humans. Only individuals who carry the ΔG allele of a genetic variant rs368234815-TT/ΔG are genetically able to produce IFN-λ4 protein. Carriers of the ΔG allele have impaired ability to clear hepatitis C virus (HCV) infection, however the mechanisms are not fully understood. Here, we used RNA-seq to evaluate the effects of IFN-λ4 and IFN-λ3 expression in inducible hepatic cell lines (HepG2) with and without the receptor (IFNLR) required for signaling of both interferons. Pathway analysis showed that despite being poorly secreted, IFN-λ4 expression induced a stronger ISG response compared to IFN-λ3. IFN-λ4 expression was also associated with reduced proliferation and increased expression of genes involved in the unfolded protein response (UPR). Subcellular localization analysis revealed that IFN-λ4 was accumulated in the Golgi and lysosomes, suggesting it is misfolded and targeted for elimination. Furthermore, intrinsic but not extrinsic expression of IFN-λ4 inhibited cell proliferation via cell cycle arrest leading to apoptosis; both indicative of UPR outcomes. In conclusion, our results show that in addition to inducing ISGs, IFN-λ4 expression induces UPR, contributing to inhibition of cell proliferation. This could have important consequences for conditions such as HCV and fibrosis, where IFN-λ4 expression has been implicated.

OR02: Interferon lambda signals to maternal tissues to limit Zika virus transplacental transmission in mice

OR02: Interferon lambda signals to maternal tissues to limit Zika virus transplacental transmission in mice

Interferon Lambda's New Role as Regulator of Neutrophil Function.

Neutrophils are increasingly appreciated as multifaceted regulators of innate immunity and inflammation. Historically, these important innate cells have been considered suicidal phagocytes with a primary role in the destruction of extracellular pathogens. Recent studies have significantly altered this simplistic view of neutrophils and have instead presented extensive evidence for a complex role for neutrophils in the control of diverse inflammatory conditions. It is now appreciated that neutrophils are crucial not only for efficient clearance of various pathogens but also in the development and control of inflammatory states such as autoimmunity, cancer, and tissue repair. Mounting evidence also suggests that neutrophils are capable of differential activation giving rise to distinctly polarized cells with diverse effector functions. Interferon lambda (IFN-λ) (also known as type III IFN) has emerged as an unexpected regulator of neutrophil function. IFN-λs are the newest members of the IFN family of antiviral cytokines and although initial studies suggested identical biological activities to type I IFNs, it is now apparent that type III IFN has distinct functions in vivo. In this article, I summarize recent evidence linking type III IFNs to the regulation and potential tailoring of neutrophil responses. These exciting observations might have important implications for the development of IFN-λs as novel therapeutic cytokines for the treatment of a diversity of inflammatory states where neutrophils are crucial players.

Interferon Lambda Inhibits Bacterial Uptake during Influenza Superinfection.

Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates morbidity and mortality from the viral illness. Recently, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with Streptococcus pneumoniae a close second. However, clinicians have few tools to treat bacterial superinfection. Current therapy for influenza/bacterial superinfection consists of treating the underlying influenza infection and adding various antibiotics, which are increasingly rendered ineffective by rising bacterial multidrug resistance. Several groups have recently proposed the use of the antiviral cytokine interferon lambda (IFN-λ) as a therapeutic for influenza, as administration of pegylated IFN-λ improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFN-λ impairs bacterial clearance during influenza superinfection. Specifically, mice treated with an adenoviral vector to overexpress IFN-λ during influenza infection exhibited increased bacterial burdens upon superinfection with either MRSA or S. pneumoniae Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFN-λ treatment. However, neutrophil uptake of MRSA and S. pneumoniae was significantly reduced upon IFN-λ treatment during influenza superinfection in vivo Together, these data support the theory that IFN-λ decreases neutrophil motility and function in the influenza-infected lung, which increases the bacterial burden during superinfection. Thus, we believe that caution should be exercised in the possible future use of IFN-λ as therapy for influenza.

Meeting Overview: Interferon Lambda-Disease Impact and Therapeutic Potential.

A meeting entitled, "Interferon Lambda: Disease Impact and Translational Potential," was held on the campus of the National Institutes of Health in Bethesda, Maryland, on October 25-26, 2018. To our knowledge, this was the first meeting that focused exclusively on interferon lambda (IFN-λ). The meeting's purpose was to enhance interdisciplinary communication and promote new collaborations. The gathering brought together an international group of scientists from a wide range of disciplines. Sessions included: IFN-λ Biology, Therapy and Genetic Variation; IFN-λ and Hepatitis C Virus Infection; IFN-λ in Other Infections; and IFN-λ-Hepatic Fibrosis and Cancer. The next meeting on IFN-λ is planned for 2020.

Host genetic factors and clinical parameters influencing the occult hepatitis C virus infection in patients on chronic hemodialysis: Is it still a controversial infection?

The presence of occult hepatitis C virus (HCV) infection (OCI) is still controversial, however, this infection cannot be ignored. Therefore, the current study aimed at assessing the OCI frequency in patients on chronic hemodialysis (CHD) and also evaluating the association between OCI incidence with clinical parameters and interferon lambda 3/4 (IFNL3/4) gene polymorphisms. A total of 515 patients on CHD and HCV negative markers were selected. Plus- and minus-stranded HCV-RNA was tested in peripheral blood mononuclear cell samples by reverse transcription-polymerase chain reaction and then genotyped using the restriction fragment length polymorphism method. The frequency of OCI was 11.3% in patients on CHD. Among 58 patients with OCI, 25.8%, 62.1%, and 12.1% were infected with HCV-1a, HCV-1b, and HCV-3a, respectively. The mean alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were 31.9 ± 24.8, 32.3 ± 19.1, and 171.6 ± 88.9, respectively. None of the patients with OCI had a history of liver disease. Multivariate logistic regression analysis indicated that cholesterol, triglyceride, low-density lipoprotein, 25-hydroxyvitamin D, platelets, duration of hemodialysis, HCV subtypes, IFNL3 rs12979860 TT, IFNL3 rs8099917 GG, IFNL3 rs12980275 GG, and IFNL4 ss469415590 ΔG/ΔG genotypes were associated with OCI. There was a moderate prevalence of OCI in Iranian patients on CHD. The current study findings indicated that this infection was associated with clinical parameters and unfavorable genotypes of IFNL3 single nucleotide polymorphisms and IFNL4 ss469415590. Further studies are required to determine the correlation between OCI incidence with clinical parameters and host genetic factors.

THU-281-Single nucleotide polymorphisms associated with no interferon lambda 4 production are associated with reduced mortality in alcoholic hepatitis

THU-281-Single nucleotide polymorphisms associated with no interferon lambda 4 production are associated with reduced mortality in alcoholic hepatitis

PS-052-End of study results from LIMT HDV study: 36% durable virologic response at 24 weeks post-treatment with pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection

PS-052-End of study results from LIMT HDV study: 36% durable virologic response at 24 weeks post-treatment with pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection

THU-204-Analysis of interleukin 28B rs12979860 polymorphism relationship with spontaneous clearance of hepatitis D virus infection in Mongolian population

THU-204-Analysis of interleukin 28B rs12979860 polymorphism relationship with spontaneous clearance of hepatitis D virus infection in Mongolian population

Peripheral blood and hepatic Toll-like receptor 7 expression and interferon lambda 1 levels in chronic hepatitis C: Relation to virus replication and liver injury

Background and aimToll-like receptor 7 (TLR7) can recognize single-stranded RNA viruses like hepatitis C virus (HCV) with subsequent induction of different interferon (IFN) types including IFN lambda (IFNL), which activate an immediate anti-viral response. However, the role of TLR7 in inflammation and fibrosis, characteristics of HCV-induced liver injury, is still controversial. The present work was designed to investigate the potential role of TLR7 and IFNL1 in chronic hepatitis C (CHC) in relation to viral replication and liver injury. MethodsForty two treatment-naïve patients with CHC and 20 healthy subjects were enrolled in the study. TLR7 expression on peripheral blood CD14+ monocytes was studied by color flow cytometry and the frequency of TLR7+CD14+ cells was expressed as percentage of total monocyte count. Quantification of IFNL1 levels in serum was determined using enzyme-linked immunosorbant assay. Liver biopsies were examined for assessment of histological activity grade (A0-A3) and fibrosis stage (F0-F4) according to METAVIR scoring system as well as steatosis grade. Immunohistochemical staining was performed using human antibodies against TLR7 and IFNL1 and was scored semi-quantitatively (score 0–3). Hepatic expression of TLR7 and IFNL1 was further classified using a two-grade scale as low expression (score 0 or 1) and high expression (score 2 or 3). ResultsPercentages of circulating TLR7+CD14+ monocytes and serum IFNL1 levels were significantly higher in patients with CHC than in healthy controls (P = 0.025 and P < 0.001 respectively) and were positively correlated with corresponding hepatic TLR7 and IFNL1 expression (P < 0.001 and P = 0.010 respectively). Significantly lower peripheral blood and hepatic TLR7 expression and IFNL1 levels were found in patients with viral loads between 200,000–600,000 IU/ml and >600,000 IU/ml than in those with viral load <200,000 IU/ml (P < 0.05), in patients with severe necroinflammation than in those with mild-to-moderate necroinflammation (P < 0.05) and in patients with advanced fibrosis than in those with early fibrosis (P < 0.01). Also, changes in TLR7 expression and IFNL1 production in peripheral blood and the liver were inversely correlated with serum levels of aspartate and alanine aminotransferases (P < 0.05) and HCV RNA (P < 0.01), histological activity grade (P < 0.01) and fibrosis stage (P < 0.01). By plotting receiver operating characteristics (ROC) curve, serum IFNL1 showed higher sensitivity and specificity than percentages of circulating TLR7+CD14+ monocytes in discriminating patients with CHC according to the severity of hepatic necroinflammation (area under the curve (AUC) = 0.901 vs. 0.816 respectively) and fibrosis (AUC = 0.971 vs. 0.825 respectively) at a cut-off value of 44.75 pg/ml and 10.25% respectively. ConclusionsTLR7 activation and IFNL1 production in CHC may play an important role in controlling viral replication and limiting hepatic inflammation and fibrosis and their downregulation may result in viral persistence and disease progression. The immunoregulatory role of TLR7-IFNL1 pathway in the pathogenesis of chronic HCV infection should be further studied. Clinical trials with a large number of patients are needed to assess the usefulness of serum IFNL1 as a potential biomarker for severity of liver injury in chronic HCV infection and other liver diseases.

Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection.

Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in 2012 as a novel etiological agent of severe respiratory disease in humans. As during infection by other viruses, host sensing of viral double-stranded RNA (dsRNA) induces several antiviral pathways. These include interferon (IFN), oligoadenylate synthetase (OAS)-RNase L, and protein kinase R (PKR). Coronaviruses, including MERS-CoV, potently suppress the activation of these pathways, inducing only modest host responses. Our study describes the functions of two accessory proteins unique to MERS-CoV and related viruses, NS4a and NS4b, during infection in human airway epithelium-derived A549 cells. NS4a has been previously characterized as a dsRNA binding protein, while NS4b is a 2',5'-phosphodiesterase with structural and enzymatic similarity to NS2 encoded by mouse hepatitis virus (MHV). We found that deletion of NS4a results in increased interferon lambda (IFNL1) expression, as does mutation of either the catalytic site or nuclear localization sequence of NS4b. All of the mutant viruses we tested exhibited slight decreases in replication. We previously reported that, like MHV NS2, NS4b antagonizes OAS-RNase L, but suppression of IFN is a previously unidentified function for viral phosphodiesterases. Unexpectedly, deletion of NS4a does not result in robust activation of the PKR or OAS-RNase L pathways. Therefore, MERS-CoV likely encodes other proteins that contribute to suppression or evasion of these antiviral innate immune pathways that should be an important focus of future work. This study provides additional insight into the complex interactions between MERS-CoV and the host immune response.IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) is the second novel zoonotic coronavirus to emerge in the 21st century and cause outbreaks of severe respiratory disease. More than 2,200 cases and 800 deaths have been reported to date, yet there are no licensed vaccines or treatments. Coronaviruses encode unique accessory proteins that are not required for replication but most likely play roles in immune antagonism and/or pathogenesis. Our study describes the functions of MERS-CoV accessory proteins NS4a and NS4b during infection of a human airway-derived cell line. Loss of these accessory proteins during MERS-CoV infection leads to host antiviral activation and modestly attenuates replication. In the case of both NS4a and NS4b, we have identified roles during infection not previously described, yet the lack of robust activation suggests much remains to be learned about the interactions between MERS-CoV and the infected host.

Changes in Serum Levels of Type-III Interferons in Ankylosing Spondylitis Treated With Tumor Necrosis Factor-Alpha Inhibitors

Changes in Serum Levels of Type-III Interferons in Ankylosing Spondylitis Treated With Tumor Necrosis Factor-Alpha Inhibitors

New treatment options for delta virus: Is a cure in sight?

Current treatment of chronic hepatitis D viral infection with interferons is poorly tolerated and effective only in a minority of patients. Despite delta virus causing the most severe form of chronic viral hepatitis, no other treatments are available. After many years of inactivity, there is now hope for new treatment approaches for delta virus and some are likely to enter clinical practice in the near future. Four new treatment approaches are currently being evaluated in phase 2 studies. These involve the hepatocyte entry inhibitor myrcludex B, the farnesyl transferase inhibitor lonafarnib, the nucleic acid inhibitor REP 2139 Ca and pegylated interferon lambda. Results obtained so far are promising, and phase 3 studies are expected shortly. This review summarizes the available data on the efficacy and safety of these new drugs.

The efficacy of adding vitamin B12 to pegylated interferon and ribavirin treatment in Hepatitis C virus patients regarding the host and viral prognostic factors

Introduction: Hepatitis C virus (HCV) infection affects almost 180 million people around the world. Even though the development of direct acting antivirals (DAAs) has significantly improved the treatment responses to HCV infection, treatment with pegylated interferon (PegIFN) in combination with ribavirin is considered the standard of care (SOC) for chronic HCV infection treatment in countries with limited medical resources. Considering the inhibitory effect of vitamin B12 on HCV replication, we have evaluated the effect of vitamin B12 supplementation along with SOC on treatment outcomes in patients with chronic HCV infection, who were antiviral treatment-naive.&#x0D; Methods: In this regard, seventy-four HCV-infected patients, naïve to antiviral therapy, were randomly assigned to receive SOC or SOC in addition to vitamin B12 (SOC + B12). Viral response was evaluated at 4, 12, 24 and 48 weeks following the initiation of viral treatment and at 24 weeks after completing the treatment. Genotyping of the interleukin 28B (IL28B) polymorphisms was also performed. Demographic characteristics, clinical findings, fibroscan results and drug adverse effects were recorded.&#x0D; Results: Our findings showed that rapid viral response was not significantly different between the two groups; however, the rates of complete early viral response (cEVR) (p=0.033), end-of-treatment viral response (ETVR) (p=0.001) and sustained virologic response (SVR) (p=0.0001) were significantly higher in SOC + B12 patients compared to SOC patients. Besides, in SOC + B12 patients, those with a higher baseline viral load and carriers of IL28B CC genotype showed significantly higher rate of SVR.&#x0D; Conclusion: In conclusion, the addition of vitamin B12 significantly improved the rate of SVR in HCV-infected patients, who were naïve to antiviral therapy. As this treatment regimen is safe and inexpensive, it proposes an option for improving the effectiveness of the HCV treatment with SOC, particularly in resource-limited settings.&#x0D;

Porcine Intestinal Enteroids: a New Model for Studying Enteric Coronavirus Porcine Epidemic Diarrhea Virus Infection and the Host Innate Response.

Porcine epidemic diarrhea virus (PEDV), a member of the group of alphacoronaviruses, is the pathogen of a highly contagious gastrointestinal swine disease. The elucidation of the events associated with the intestinal epithelial response to PEDV infection has been limited by the absence of good in vitro porcine intestinal models that recapitulate the multicellular complexity of the gastrointestinal tract. Here, we generated swine enteroids from the intestinal crypt stem cells of the duodenum, jejunum, or ileum and found that the generated enteroids are able to satisfactorily recapitulate the complicated intestinal epithelium in vivo and are susceptible to infection by PEDV. PEDV infected multiple types of cells, including enterocytes, stem cells, and goblet cells, and exhibited segmental infection discrepancies compared with ileal enteroids and colonoids, and this finding was verified in vivo Moreover, the clinical isolate PEDV-JMS propagated better in ileal enteroids than the cell-adapted isolate PEDV-CV777, and PEDV infection suppressed interferon (IFN) production early during the infection course. IFN lambda elicited a potent antiviral response and inhibited PEDV in enteroids more efficiently than IFN alpha (IFN-α). Therefore, swine enteroids provide a novel in vitro model for exploring the pathogenesis of PEDV and for the in vitro study of the interplay between a host and a variety of swine enteric viruses.IMPORTANCE PEDV is a highly contagious enteric coronavirus that causes significant economic losses, and the lack of a good in vitro model system is a major roadblock to an in-depth understanding of PEDV pathogenesis. Here, we generated a porcine intestinal enteroid model for PEDV infection. Utilizing porcine intestinal enteroids, we demonstrated that PEDV infects multiple lineages of the intestinal epithelium and preferably infects ileal enteroids over colonoids and that enteroids prefer to respond to IFN lambda 1 over IFN-α. These events recapitulate the events that occur in vivo This study constitutes the first use of a primary intestinal enteroid model to investigate the susceptibility of porcine enteroids to PEDV and to determine the antiviral response following infection. Our study provides important insights into the events associated with PEDV infection of the porcine intestine and provides a valuable in vitro model for studying not only PEDV but also other swine enteric viruses.

Dynamic Expression of Interferon Lambda Regulated Genes in Primary Fibroblasts and Immune Organs of the Chicken.

Interferons (IFNs) are pleiotropic cytokines that establish a first line of defense against viral infections in vertebrates. Several types of IFN have been identified; however, limited information is available in poultry, especially using live animal experimental models. IFN-lambda (IFN-λ) has recently been shown to exert a significant antiviral impact against viral pathogens in mammals. In order to investigate the in vivo potential of chicken IFN-λ (chIFN-λ) as a regulator of innate immunity, and potential antiviral therapeutics, we profiled the transcriptome of chIFN-λ-stimulated chicken immune organs (in vivo) and compared it with primary chicken embryo fibroblasts (in vitro). Employing the baculovirus expression vector system (BEVS), recombinant chIFN-λ3 (rchIFN-λ3) was produced and its biological activities were demonstrated. The rchIFNλ3 induced a great array of IFN-regulated genes in primary chicken fibroblast cells. The transcriptional profiling using RNA-seq and subsequent bioinformatics analysis (gene ontology, differential expressed genes, and KEGGs analysis) of the bursa of Fabricious and the thymus demonstrated an upregulation of crucial immune genes (viperin, IKKB, CCL5, IL1β, and AP1) as well as the antiviral signaling pathways. Interestingly, this experimental approach revealed contrasting evidence of the antiviral potential of chIFN-λ in both in vivo and in vitro models. Taken together, our data signifies the potential of chIFN-λ as a potent antiviral cytokine and highlights its future possible use as an antiviral therapeutic in poultry.

Association of serum interferon-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents.

Although the efficacy of hepatitis C virus (HCV) treatment is improved dramatically by direct-acting antiviral agents (DAAs), the assessment of hepatocellular carcinoma (HCC) remains important. Interferon lambda 3 (IFN-λ3) is associated with liver fibrosis and inflammation in chronic hepatitis C (CHC) patients, but its impact on carcinogenesis remains controversial and little is known about its effects after viral clearance. To determine the contribution of IFN-λ3 to hepatocarcinogenesis after HCV clearance, we analyzed IFNL3 genotypes and serial serum IFN-λ3 levels in CHC patients who achieved sustained virologic responses (SVR). This study comprised 201 CHC patients treated with DAAs. Serum samples were collected sequentially and IFN-λ3 levels were quantified by chemiluminescence enzyme immunoassay. The IFNL3 polymorphism (rs8099917) was genotyped in 195 patients. One hundred and twenty-five patients were rs8099917 T/T and 70 were non-T/T. Serum IFN-λ3 levels did not differ significantly with IFNL3 genotype, dropped markedly by 1week and remained low up to 24weeks after the end of treatment. Interferon-λ3 levels were significantly higher after viral clearance in patients who developed HCC and were associated with a higher potential for hepatocarcinogenesis, such as a higher frequency of non-hypervascular hypointensive nodules (P = 0.046), higher stages of liver fibrosis (P < 0.001), and higher post-treatment levels of Wisteria floribunda agglutinin positive Mac-2 binding protein (P < 0.001) and alanine aminotransferase (P < 0.001). Serum IFN-λ3 levels after HCV clearance are associated with the potential for HCC development. Interferon-λ3 could be helpful for elucidating the relationships among immunologic status, liver fibrosis, liver inflammation, and hepatocarcinogenesis, after achieving SVR.

Influenza Vaccination Induces NK-Cell-Mediated Type-II IFN Response that Regulates Humoral Immunity in an IL-6-Dependent Manner

The role of natural killer (NK) cells in the immune response against vaccines is not fully understood. Here, we examine the function of infiltrated NK cells in the initiation of the inflammatory response triggered by inactivated influenza virus vaccine in the draining lymph node (LN). We observed that, following vaccination, NK cells are recruited to the interfollicular and medullary areas of the LN and become activated by type I interferons (IFNs) produced by LN macrophages. The activation of NK cells leads to their early production of IFNγ, which in turn regulates the recruitment of IL-6+ CD11b+ dendritic cells. Finally, we demonstrate that the interleukin-6 (IL-6)-mediated inflammation is important for the development of an effective humoral response against influenza virus in the draining LN.

The KH-type splicing regulatory protein (KSRP) regulates type III interferon expression post-transcriptionally.

Type III interferons (IFNs) are the latest members of the IFN family. They play an important role in immune defense mechanisms, especially in antiviral responses at mucosal sites. Moreover, they control inflammatory reactions by modulating neutrophil and dendritic cell functions. Therefore, it is important to identify cellular mechanisms involved in the control of type III IFN expression. All IFN family members contain AU-rich elements (AREs) in the 3'-untranslated regions (3'-UTR) of their mRNAs that determine mRNA half-life and consequently the expressional level of these cytokines. mRNA stability is controlled by different proteins binding to these AREs leading to either stabilization or destabilization of the respective target mRNA. The KH-type splicing regulatory protein KSRP (also named KHSRP) is an important negative regulator of ARE-containing mRNAs. Here, we identify the interferon lambda 3 (IFNL3) mRNA as a new KSRP target by pull-down and immunoprecipitation experiments, as well as luciferase reporter gene assays. We characterize the KSRP-binding site in the IFNL3 3'-UTR and demonstrate that KSRP regulates the mRNA half-life of the IFNL3 transcript. In addition, we detect enhanced expression of IFNL3 mRNA in KSRP-/- mice, establishing a negative regulatory function of KSRP in type III IFN expression also in vivo Besides KSRP the RNA-binding protein AUF1 (AU-rich element RNA-binding protein 1) also seems to be involved in the regulation of type III IFN mRNA expression.