RESUMO
The cytokine interleukin-22 (IL-22), which is a member of the IL-10 family, is produced exclusively by immune cells and activates signal transducer and activator of transcription 3 (STAT3) in nonimmune cells, such as hepatocytes, keratinocytes, and colonic epithelial cells, to drive various processes central to tissue homeostasis and immunosurveillance. Dysregulation of IL-22 signaling causes inflammatory diseases. IL-22 binding protein (IL-22BP; encoded by IL22RA2) is a soluble IL-22 receptor, which antagonizes IL-22 activity and has genetic associations with autoimmune diseases. Humans have three IL-22BP isoforms, IL-22BPi1 to IL-22BPi3, which are generated by alternative splicing; mice only have an IL-22BPi2 homolog. We showed that, although IL-22BPi3 had less inhibitory activity than IL-22BPi2, IL-22BPi3 was more abundant in various human tissues under homeostatic conditions. IL-22BPi2 was more effective than IL-22BPi3 at blocking the contribution of IL-22 to cooperative gene induction with the inflammatory cytokine IL-17, which is often present with IL-22 in autoimmune settings. In addition, we found that IL-22BPi1 was not secreted and therefore failed to antagonize IL-22 signaling. Furthermore, IL-22BPi2 was the only isoform that was increased in abundance when myeloid cells were activated by Toll-like receptor 2 signaling or retinoic acid, a maturation factor for myeloid cells. These data suggest that the human IL-22BP isoforms have distinct spatial and temporal roles and coordinately fine-tune IL-22-dependent STAT3 responses in tissues as a type of rheostat.
Assuntos
Processamento Alternativo/imunologia , Interleucinas/imunologia , Receptores de Interleucina/imunologia , Transdução de Sinais/imunologia , Células CACO-2 , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Interleucinas/genética , Masculino , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Receptores de Interleucina/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/genética , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Interleucina 22RESUMO
Interferon (IFN) lambdas are critical antiviral effectors in hepatic and mucosal infections. Although IFNλ1, IFNλ2, and IFNλ3 act antiviral, genetic association studies have shown that expression of the recently discovered IFNL4 is detrimental to hepatitis C virus (HCV) infection through a yet unknown mechanism. Intriguingly, human IFNL4 harbors a genetic variant that introduces a premature stop codon. We performed a molecular and biochemical characterization of IFNλ4 to determine its role and regulation of expression. We found that IFNλ4 exhibits similar antiviral activity to IFNλ3 without negatively affecting antiviral IFN activity or cell survival. We show that humans deploy several mechanisms to limit expression of functional IFNλ4 through noncoding splice variants and nonfunctional protein isoforms. Furthermore, protein-coding IFNL4 mRNA are not loaded onto polyribosomes and lack a strong polyadenylation signal, resulting in poor translation efficiency. This study provides mechanistic evidence that humans suppress IFNλ4 expression, suggesting that immune function is dependent on other IFNL family members.
Assuntos
Interações Hospedeiro-Patógeno , Interleucinas/metabolismo , Viroses/metabolismo , Processamento Alternativo/genética , Animais , Antivirais/farmacologia , Sequência de Bases , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Espaço Extracelular/metabolismo , Mutação da Fase de Leitura/genética , Hepacivirus/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Interferons , Interleucinas/farmacologia , Espaço Intracelular/metabolismo , Modelos Biológicos , Moléculas com Motivos Associados a Patógenos/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , Receptores de Citocinas/metabolismo , Receptores de Interferon , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection.