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INTERLEUKIN 29
LATEST LITERATURE
1: Cytokine & growth factor reviews, 2010 Jul 22,
IL-28A, IL-28B, and IL-29: Promising cytokines with type I interferon-like properties.
[Abstract]IL-28A, IL-28B and IL-29 (also designated type III interferons) constitute a new subfamily within the IL-10-interferon family. They are produced by virtually any nucleated cell type, particularly dendritic cells, following viral infection or activation with bacterial components, and mediate their effects via the IL-28R1/IL-10R2 receptor complex. Although IL-28/IL-29 are closer to the IL-10-related cytokines in terms of gene structure, protein structure, and receptor usage, they display type I interferon-like anti-viral and cytostatic activities. Unlike type I interferons, the target cell populations of IL-28/IL-29 are restricted and mainly include epithelial cells and hepatocytes. These properties suggest that IL-28/IL-29 are potential therapeutic alternatives to type I interferons in terms of viral infections and tumors. This review describes the current knowledge about these cytokines.
2: Journal of virology, 2010 Jun 30,
IFN-{alpha}/{beta}-independent induction of IFN-{lambda}1 (IL-29) in response to Hantaan virus infection.
[Abstract]Type III IFNs (IFN-lambda/IL-28/29) are recently recognized cytokines with innate antiviral effects similar to those of type I IFNs (IFN-alpha/beta). Like IFN-alpha/beta, IFN-lambda-expression can be induced by viruses, and it is believed that type I and III IFNs are regulated in the same manner. Hantaviruses are weak IFN-alpha/beta-inducers and have surprisingly been shown to activate IFN-alpha/beta-independent ISG-expression. Here we show that in Hantaan virus (HTNV) infected human epithelial A549 cells, induction of IFN-lambda1 preceded induction of MxA and IFN-beta by 12 and 24 hours, respectively, and IFN-alpha was not induced at all. Furthermore, induction of IFN-lambda1 and MxA was observed in HTNV-infected African green monkey epithelial Vero E6 cells, a cell line that cannot produce type I IFNs, clearly showing that HTNV can induce IFN-lambda1 and ISGs in the complete absence of IFN-alpha/beta. In HTNV-infected human fibroblast MRC-5 cells, which lack the IFN-lambda receptor, induction of MxA coincided in time with IFN-beta-induction. UV-inactivated HTNV did not induce any IFNs or MxA in any cell line, showing that activation of IFN-lambda1 is dependent on replicating virus. Induction of both IFN-beta and IFN-lambda1 in A549 cells after poly I:C-stimulation were strongly inhibited in HTNV-infected cells, suggesting that HTNV can inhibit signaling pathways used to simultaneously activate type I and III IFNs. In conclusion, we show that HTNV can cause type I IFN-independent IFN-lambda1-induction and IFN-lambda1 specific ISG-induction. Importantly, the results suggest the existence of specific signaling pathways that induce IFN-lambda1 without simultaneous type I IFN-induction during virus infection.
3: Allergy, 2010 Mar 22,
Expression and release of IL-29 by mast cells and modulation of mast cell behavior by IL-29.
[Abstract]To cite this article: He S, Zhang H, Chen H, Yang H, Huang T, Chen Y, Lin J, Wang F, Chen X, Li T-L, Yang P. Expression and release of IL-29 by mast cells and modulation of mast cell behavior by IL-29. Allergy 2010; DOI: 10.1111/j.1398-9995.2010.02349.x. Abstract Background: The role of interleukin (IL)-29 in innate immunity has been recognized recently, and it is regarded as a potent bioactive molecule. However, little is known about its role in the pathogenesis of allergy. Because mast cells are recognized as primary effector cells of allergy, we investigated the potential relationship between IL-29 and mast cells in this study. Objective: To examine the expression of IL-29 in mast cells and the influence of IL-29 on mast cell mediator release and accumulation. Methods: Expression of IL-29 in mast cells was determined by double-labeling immunohistochemistry and flow cytometry analysis. Mast cell cell-line was cultured to examine the mediator release, and mouse peritoneal model was employed to observe the mast cell accumulation. Results: Large proportions of mast cells expressing IL-29 were localized in human tissue including the colon, tonsil and lung. Mast cells can release substantial quantity of IL-29 upon challenge with proteolytic allergens. Extrinsic IL-29 provoked IL-4 and IL-13 release from mast cell line P815 cells through PI3K/Akt and (JAK)/STAT3 signaling pathways, but failed to induce mast cell histamine release from human mast cells. Extrinsic IL-29 also induced mast cell infiltration in mouse peritoneum by a CD18- and ICAM1-dependent mechanism. Conclusion: Mast cell-derived IL-29 has the potential to be involved in the pathogenesis of allergic inflammation.
4: Molecular cancer therapeutics, 2010 Jan 26,
Interleukin-29 Binds to Melanoma Cells Inducing Jak-STAT Signal Transduction and Apoptosis.
[Abstract]Interleukin-29 (IL-29) is a member of the type III IFN family that has been shown to have antiviral activity and to inhibit cell growth. Melanoma cell lines were tested for expression of the IL-29 receptor (IL-29R) and their response to IL-29. Expression of IL-28R1 and IL-10R2, components of IL-29R, was evaluated using reverse transcription-PCR. A combination of immunoblot analysis and flow cytometry was used to evaluate IL-29-induced signal transduction. U133 Plus 2.0 Arrays and real-time PCR were used to evaluate gene expression. Apoptosis was measured using Annexin V/propridium iodide staining. In situ PCR for IL-29R was done on paraffin-embedded melanoma tumors. Both IL-28R1 and IL-10R2 were expressed on the A375, 1106 MEL, Hs294T, 18105 MEL, MEL 39, SK MEL 5, and F01 cell lines. Incubation of melanoma cell lines with IL-29 (10-1,000 ng/mL) led to phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2. Microarray analysis and quantitative reverse transcription-PCR showed a marked increase in transcripts of IFN-regulated genes after treatment with IL-29. In the F01 cell line, bortezomib-induced and temozolomide-induced apoptosis was synergistically enhanced following the addition of IL-29. In situ PCR revealed that IL-10R2 and IL-28R1 were present in six of eight primary human melanoma tumors but not in benign nevi specimens. In conclusion, IL-29 receptors are expressed on the surface of human melanoma cell lines and patient samples, and treatment of these cell lines with IL-29 leads to signaling via the Jak-STAT pathway, the transcription of a unique set of genes, and apoptosis. Mol Cancer Ther; 9(2); OF1-11.
5: Journal of leukocyte biology, 2009 Sep 16,
Modulation of human plasmacytoid DC function by IFN-{lambda}1 (IL-29).
[Abstract]The type III family of IFNs displays immunomodulatory and antiviral activity. Each member (IFN-lambda1, -2, and -3) signals through the same heterodimeric receptor complex, which consists of the binding and signaling subunit (IL-28Ralpha) plus the IL-10Rbeta chain. Although the receptor has a wide tissue distribution, the direct effects of IFN-lambda on various immune cell subsets have not been fully characterized. We have identified high levels of IL-28Ralpha mRNA in pDC from peripheral blood and hypothesized that IFN-lambda plays an important role in pDC maturation and development. We show that stimulation of pDC with HSV or Imiquimod causes an increase in IL-28Ralpha mRNA. In these cells, IFN-lambda1 alters expression of the costimulatory molecules CD80 and ICOS-L and synergizes with IFN-alpha to up-regulate CD83. In addition, IFN-lambda1 has a variable effect on the homing molecule expression of pDC and mDC. IFN-lambda1-treated pDC display a marked difference in their ability to stimulate production of the signature cytokines IL-13, IFN-gamma, and IL-10 in a MLR. This work characterizes the variable effects of IFN-lambda on DC surface molecule expression and identifies a role in pDC activation and immunostimulatory potential.
6: Blood, 2009 Jun 4, 113(23)
IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses Th2 responses in human naive and memory T cells.
[Abstract]IFN-lambda1 (IL-29) plays a novel, emerging role in the inhibition of human Th2 responses. Here, we demonstrate that both naive and memory human CD4(+) T cells express mRNA for the IFN-lambda1-specific receptor, IL-28Ralpha, and are responsive to IFN-lambda1. Expression of Th2 cytokines (IL-4 and IL-13) was suppressed in naive and memory CD4(+) T cells by IFN-lambda1, without affecting their proliferation. Further, acquisition of IL-4Ralpha expression after stimulation was inhibited by IFN-lambda1, as was GATA3 expression. Finally, IFN-lambda1 diminished the change in cell-surface phenotype that accompanies differentiation of "central memory" T cells into "effector memory" T cells. Taken together, our data describe unique immunomodulatory effects of IFN-lambda1 and identify novel mechanisms for the reduction of existing Th2 responses and the regulation of new ones, in circulating naive and memory CD4(+) T cells.
7: Journal of immunology (Baltimore, Md. : 1950), 2009 Feb 1, 182(3)
Differentiated human alveolar type II cells secrete antiviral IL-29 (IFN-lambda1) in response to influenza A infection.
[Abstract]Alveolar type II epithelial cells (ATIIs) are one of the primary targets for influenza A pneumonia. The lack of a culture system for maintaining differentiated ATIIs hinders our understanding of pulmonary innate immunity during viral infection. We studied influenza A virus (IAV)-induced innate immune responses in differentiated primary human ATIIs and alveolar macrophages (AMs). Our results indicate that ATIIs, but not AMs, support productive IAV infection. Viral infection elicited strong inflammatory chemokine and cytokine responses in ATIIs, including secretion of IL-8, IL-6, MCP-1, RANTES, and MIP-1beta, but not TNF-alpha, whereas AMs secreted TNF-alpha as well as other cytokines in response to infection. Wild-type virus A/PR/8/34 induced a greater cytokine response than reassortant PR/8 virus, A/Phil/82, despite similar levels of replication. IAV infection increased mRNA expression of IFN genes IFN-beta, IL-29 (IFN-lambda1), and IL-28A (IFN-lambda2). The major IFN protein secreted by type II cells was IL-29 and ATIIs appear to be a major resource for production of IL-29. Administration of IL-29 and IFN-beta before infection significantly reduced the release of infectious viral particles and CXC and CC chemokines. IL-29 treatment of type II cells induced mRNA expression of antiviral genes MX1, OAS, and ISG56 but not IFN-beta. IL-29 induced a dose-dependent decrease of viral nucleoprotein and an increase of antiviral genes but not IFN-beta. These results suggest that IL-29 exerts IFN-beta-independent protection in type II cells through direct activation of antiviral genes during IAV infection.
8: The Journal of biological chemistry, 2008 Oct 31, 283(44)
Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication.
[Abstract]The interferon (IFN)-related cytokine interleukin (IL)-29 (also known as IFN-lambda1) inhibits virus replication by inducing a cellular antiviral response similar to that activated by IFN-alpha/beta. However, because it binds to a unique receptor, this cytokine may function cooperatively with IFN-alpha/beta or IFN-gamma during natural infections to inhibit virus replication, and might also be useful therapeutically in combination with other cytokines to treat chronic viral infections such as hepatitis C (HCV). We therefore investigated the ability of IL-29 and IFN-alpha or IFN-gamma to cooperatively inhibit virus replication and induce antiviral gene expression. Compared with the individual cytokines alone, the combination of IL-29 with IFN-alpha or IFN-gamma was more effective at blocking vesicular stomatitis virus and HCV replication, and this cooperative antiviral activity correlated with the magnitude of induced antiviral gene expression. Although the combined effects of IL-29 and IFN-alpha were primarily additive, the IL-29/IFN-gamma combination synergistically induced multiple genes and had the greatest antiviral activity. Two different mechanisms contributed to the enhanced gene expression induced by the cytokine combinations: increased activation of ISRE promoter elements and simultaneous activation of both ISRE and GAS elements within the same promoter. These findings provide new insight into the coregulation of a critical innate immune response by functionally distinct cytokine families.
9: Immunology, 2008 Dec, 125(4)
Interferon-lambda1 (interleukin-29) preferentially down-regulates interleukin-13 over other T helper type 2 cytokine responses in vitro.
[Abstract]Interferon (IFN)-lambda1 [interleukin (IL)-29] is a member of the interferon lambda family (also known as type III interferons), whose members are distantly related to both the type I interferons and members of the IL-10 family. While IFN-lambda1 has significant antiviral activity, it is also becoming apparent that it has important immunoregulatory properties, especially with regard to the T helper type 2 (Th2) response. Previously, we have shown that IFN-lambda1 is capable of down-regulating IL-13 production in an IFN-gamma-independent manner and that this is mediated in part via monocyte-derived dendritic cells. Here, we have extended our knowledge of IFN-lambda1 regulation of the human in vitro Th2 response by examining the regulation of three major Th2 cytokines, IL-4, IL-5 and IL-13, by IFN-lambda1. Our results reveal that IFN-lambda1 preferentially inhibits IL-13 production, compared with IL-4 or IL-5. Levels of IL-13 mRNA, the amount of secreted IL-13 protein and numbers of IL-13-positive CD3(+) CD4(+) cells were all significantly diminished by IFN-lambda1. IFN-lambda1 significantly decreased some aspects of IL-4 and IL-5 production, but its effects were not as consistent as those seen on IL-13. IFN-lambda1 was also effective at decreasing IL-13 secretion under conditions designed to support the generation of Th2 cells. Irrespective of whether Concanavalin-A or T-cell-stimulatory microbeads were used, IFN-lambda1 markedly diminished IL-13 secretion in cultures where IL-4 had been added. Thus, IFN-lambda1 appears to be an inhibitor of human Th2 responses whose action is primarily directed towards IL-13 but which may also affect Th2 responses generally and does not invoke a complementary elevation of IFN-gamma secretion.
10: The Journal of allergy and clinical immunology, 2008 May, 121(5)
The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29.
[Abstract]Cytokines are involved in virtually every aspect of immunity and inflammation. A cascade of responses evolves after cytokine activation, although optimal function might ultimately involve several complementary cytokines. Understanding the function of individual cytokines is complicated because their role can vary depending on the cellular source, target, and phase of the immune response. In fact, numerous cytokines have both proinflammatory and anti-inflammatory potential, with the contrasting outcome observed being determined by the immune cells present and their state of responsiveness to the cytokine. These issues make the study of cytokine biology daunting, particularly so for IL-10 and IL-10-related genes. The IL-10 superfamily is highly pleiotropic. These genes are linked together through genetic similarity and intron-exon gene structure. Significant commonality exists not only through shared receptors but also through conserved signaling cascades. However, its members mediate diverse activities, including immune suppression, enhanced antibacterial and antiviral immunity, antitumor activity, and promotion of self-tolerance in autoimmune diseases.
11: Journal of leukocyte biology, 2008 May, 83(5)
Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes.
[Abstract]IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29 are new members of the IL-10 interferon family. Monocytes are well-known sources of IL-19, IL-20, and IL-24. We demonstrated here that monocytes also expressed IL-29, and monocyte differentiation into macrophages (Mphi) or dendritic cells (DCs) strongly changed their production capacity of these cytokines. Maturation of DCs with bacterial stimuli induced high expression of IL-28/IL-29 and IL-20. Simulated T cell interaction and inflammatory cytokines induced IL-29 and IL-20 in maturing DCs, respectively. Compared with monocytes, DCs expressed only minimal IL-19 levels and no IL-24. The differentiation of monocytes into Mphi reduced their IL-19 and terminated their IL-20, IL-24, and IL-29 production capacity. Like monocytes, neither Mphi nor DCs expressed IL-22 or IL-26. The importance of maturing DCs as a source of IL-28/IL-29 was supported by the much higher mRNA levels of these mediators in maturing DCs compared with those in CMV-infected fibroblasts, and the presence of IL-28 in lymph nodes but not in liver of lipopolysaccharide-injected mice. IL-19, IL-20, IL-22, IL-24, and IL-26 do not seem to affect Mphi or DCs as deduced from the lack of corresponding receptor chains. The significance of IL-20 and IL-28/IL-29 coexpression in maturing DCs may lie in the broadly amplified innate immunity in neighboring tissue cells like keratinocytes. In fact, IL-20 induced the expression of antimicrobial proteins, whereas IL-28/IL-29 enhanced the expression of toll-like receptors (TLRs) and the response to TLR ligands. However, the strongest response to TLR2 and TLR3 activation showed keratinocytes in the simultaneous presence of IL-20 and IL-29.
12: Biochimie, 2007 Jun-Jul, 89(6-7)
IL-28 and IL-29: newcomers to the interferon family.
[Abstract]IL-28 and IL-29 were recently described as members of a new cytokine family that shares with type I interferon (IFN) the same Jak/Stat signalling pathway driving expression of a common set of genes. Accordingly, they have been named IFN lambda. IFNs lambda exhibit several common features with type I IFNs: antiviral activity, antiproliferative activity and in vivo antitumour activity. Importantly, however, IFNs lambda bind to a distinct membrane receptor, composed of IFNLR1 and IL10R2. This specific receptor usage suggests that this cytokine family does not merely replicate the type I IFN system and justifies its designation as type III IFN by the nomenclature committee of the International Society of Interferon and Cytokine Research.
13: Genes and immunity, 2007 Apr, 8(3)
Human interferon lambda-1 (IFN-lambda1/IL-29) modulates the Th1/Th2 response.
[Abstract]Interferon lambda-1 (IFN-lambda1/IL-29) is a member of the Type-III interferon family, which contains three ligands: IFN-lambda1, 2 and 3. These three ligands use the same unique heterodimeric receptor composed of CRF2-12 (IFN-lambda-R1/IL-28Ralpha) and CRF2-4 (IL10-R-beta) chains. Like their close relatives, the Type-I interferons, IFN-lambda1, 2 and 3, promote the phosphorylation of STAT1 and STAT2, induce the ISRE3 complex, elevate OAS and MxA expression and exhibit antiviral activity in vitro. Their use of the IL10-R-beta chain and their ability to phosphorylate STAT3, STAT4 and STAT5 suggested that they may also exhibit immunomodulatory activity; their antiviral action led us to hypothesize that this activity might be directed toward the Th1/Th2 system. Here, we have demonstrated that IFN-lambda1 altered the activity of Th cells in three separate experimental systems: (i) mitogen stimulation, (ii) mixed-lymphocyte reaction (MLR) and (iii) stimulation of naive T cells by monocyte-derived dendritic cells (mDC). In Con-A stimulation assays, the inclusion of IFN-lambda1 consistently led to markedly diminished levels of secreted interleukin (IL-13) with occasional coincident, modest elevation of secreted IFN-gamma. IL-13 secretion was 100-fold more sensitive to IFN-lambda1 than was IFN-gamma secretion. These observations were also made in the allogeneic two-way MLR. IFN-lambda1 was able to alter cytokine-mediated Th biasing and when naive T cells were exposed to allogeneic mDC that had been matured in the presence of IFN-lambda1, secreted IL-13 was again markedly and consistently reduced, whereas secreted IFN-gamma was largely unaltered. These functions were independent of IL-10. Our data support a hitherto unsuspected role for IFN-lambda1 in modulating the development of Th1 and Th2 cells, with an apparent emphasis on the diminution of IL-13 secretion.
14: Genes and immunity, 2007 Jan, 8(1)
Modulation of the human cytokine response by interferon lambda-1 (IFN-lambda1/IL-29).
[Abstract]The interferon lambda family (IFN-lambda1/2/3) is a newly described group of cytokines that are related to both the type-1 interferons and IL-10 family members. These novel cytokines are induced during viral infection and, like type-1 interferons, display significant anti-viral activity. In order to understand their function in more depth, we have examined the ability of IFN-lambda1/IL-29 to regulate cytokine production by human immune cells. Whole peripheral blood mononuclear cells (PBMC) exposed to IFN-lambda1 specifically upregulated IL-6, -8 and -10 but there were no visible effects on TNF or IL-1. This response was produced in a dose-dependant fashion and was inhibited by IL-10. Examination of purified cell populations isolated from PBMC demonstrated that monocytes, rather than lymphocytes, were the major IFN-lambda1-responsive cellular subset, producing IL-6, -8 and -10 in response to IFN-lambda1. Monocyte responses induced by low-level LPS stimulation were also synergistically enhanced by the presence of IFN-lambda1. Human macrophages were also shown to react to IFN-lambda1 similarly to monocytes, by producing the cytokines IL-6, -8 and -10. In conclusion, we have shown that IFN-lambda1, a cytokine produced in response to viral infection, activates both monocytes and macrophages producing a restricted panel of cytokines and may therefore be important in activating innate immune responses at the site of viral infection.
15: Acta pharmacologica Sinica, 2006 Apr, 27(4)
Liposome-mediated IL-28 and IL-29 expression in A549 cells and anti-viral effect of IL-28 and IL-29 on WISH cells.
[Abstract]AIM: To construct the recombinant vectors carrying interleukin (IL)-28A, IL-28B and IL-29 cDNAs and express them in human A549 cells, and analyze their antiviral activity in vesicular stomatitis virus (VSV)-infected human immortalized amnion epithelial cell line (WISH cells). METHODS: Total cell RNA was extracted from human peripheral blood mononuclear cells (PBMC) activated with poly I:C. The cDNAs encoding human IL-28A, IL-28B, and IL-29 were amplified by reverse-transcription polymerase chain reaction (RT-PCR) and inserted into pcDNA3.1/V5-His-TOPO vectors. These recombinant vectors were transfected into human A549 cells by a liposome-mediated gene transfer method. Semiquantitative RT-PCR and Western blotting were used to detect the mRNA and protein expression of IL-28A, IL-28B, and IL-29. The antiviral activity of IL-28A, IL-28B, and IL-29 was determined by a cytopathic effect reduction assay on WISH cells using VSV as a challenge virus. RESULTS: The DNA sequences of the inserts were identical to the published sequences encoding IL-28A, IL-28B, and IL-29 in GenBank. It was demonstrated that IL-28A, IL-28B, and IL-29 genes were markedly transcribed in transfected cells. Expression of all 3 interleukins in A549 cells was confirmed by Western blot analysis. IL-28 and IL-29 expressed by A549 cells, like interferon (IFN) alpha-2b, were able to protect WISH cells against VSV infection. CONCLUSION: IL-28 and IL-29 cDNAs were successfully cloned and expressed in eukaryotic cells via transfection with pcDNA3.1/V5-His-TOPO-IL-28/IL-29. Transfection with this vector produced a specific antiviral activity similar to that of IFN-alpha, which will provide a new tool for the functional study of these cytokines in humans.
16: Journal of biotechnology, 2006 Apr 10, 122(3)
Purification and characterization of recombinant human interleukin-29 expressed in Escherichia coli.
[Abstract]Human interleukin (IL)-29 is the latest member of the class II cytokine family. However, as a result of lacking efficient method to generate relatively large quantity of IL-29, little is known of its functions in man. In the present study, an Escherichia coli expression system for the rapid expression of the human IL-29 gene was developed. It involved of cloning IL-29 gene into the pET-44 Ek/LIC vector, which allowed expression of IL-29 with a fusion tag consisting of the NusA protein, polyhistidine and S peptide (Nus-His-S-tag), and introducing a thrombin recognition site between the fusion tag and IL-29. The expressed fusion protein was purified by S-protein agarose affinity chromatography, and the fusion tag was removed from recombinant IL-29 by cleavage with thrombin. The purified IL-29 appeared a single band on SDS-PAGE, and the yield of IL-29 was 60 mg from 1 l of bacterial culture. N-terminal sequencing confirmed the identity of the purified protein. The recombinant IL-29 showed specific antiviral activity that was comparable to the commercially available IFN alfa-2b preparation.
17: Journal of virology, 2005 Aug, 79(15)
Gene expression and antiviral activity of alpha/beta interferons and interleukin-29 in virus-infected human myeloid dendritic cells.
[Abstract]Dendritic cells (DCs) respond to microbial infections by undergoing phenotypic maturation and by producing multiple cytokines. In the present study, we analyzed the ability of influenza A and Sendai viruses to induce DC maturation and activate tumor necrosis factor alpha (TNF-alpha), alpha/beta interferon (IFN-alpha/beta), and IFN-like interleukin-28A/B (IFN-lambda2/3) and IL-29 (IFN-lambda1) gene expression in human monocyte-derived myeloid DCs (mDC). The ability of influenza A virus to induce mDC maturation or enhance the expression of TNF-alpha, IFN-alpha/beta, interleukin-28 (IL-28), and IL-29 genes was limited, whereas Sendai virus efficiently induced mDC maturation and enhanced cytokine gene expression. Influenza A virus-induced expression of TNF-alpha, IFN-alpha, IFN-beta, IL-28, and IL-29 genes was, however, dramatically enhanced when cells were pretreated with IFN-alpha. IFN-alpha priming led to increased expression of Toll-like receptor 3 (TLR3), TLR7, TLR8, MyD88, TRIF, and IFN regulatory factor 7 (IRF7) genes and enhanced influenza-induced phosphorylation and DNA binding of IRF3. Influenza A virus also enhanced the binding of NF-kappaB to the respective NF-kappaB elements of the promoters of IFN-beta and IL-29 genes. In mDC IL-29 induced MxA protein expression and possessed antiviral activity against influenza A virus, although this activity was lower than that of IFN-alpha or IFN-beta. Our results show that in human mDCs viruses can readily induce the expression of IL-28 and IL-29 genes whose gene products are likely to contribute to the host antiviral response.
18: Journal of immunology (Baltimore, Md. : 1950), 2005 Feb 15, 174(4)
IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29.
[Abstract]Toll-like receptors (TLRs) mediate host cell activation by various microbial components. TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 are the receptors that have been associated with virus-induced immune response. We have previously reported that all these TLRs, except TLR9, are expressed at mRNA levels in human monocyte-derived macrophages. Here we have studied TLR2, TLR3, TLR4, and TLR7/8 ligand-induced IFN-alpha, IFN-beta, IL-28, and IL-29 expression in human macrophages. IFN-alpha pretreatment of macrophages was required for efficient TLR3 and TLR4 agonist-induced activation of IFN-alpha, IFN-beta, IL-28, and IL-29 genes. TLR7/8 agonist weakly activated IFN-alpha, IFN-beta, IL-28, and IL-29 genes, whereas TLR2 agonist was not able to activate these genes. IFN-alpha enhanced TLR responsiveness in macrophages by up-regulating the expression of TLR3, TLR4, and TLR7. IFN-alpha also enhanced the expression of TLR signaling molecules MyD88, TIR domain-containing adaptor inducing IFN-beta, IkappaB kinase-epsilon, receptor interacting protein 1, and IFN regulatory factor 7. Furthermore, the activation of transcription factor IFN regulatory factor 3 by TLR3 and TLR4 agonists was dependent on IFN-alpha pretreatment. In conclusion, our results suggest that IFN-alpha sensitizes cells to microbial recognition by up-regulating the expression of several TLRs as well as adapter molecules and kinases involved in TLR signaling.
19: International journal of immunopathology and pharmacology, 2004 May-Aug, 17(2)
Interleukin-28 and 29 (IL-28 and IL-29): new cytokines with anti-viral activities.
[Abstract]Interferon (IFN)-lambda 1, -lambda 2, and -lambda 3 are the latest members of the class II cytokine family and were shown to have antiviral activity. Their receptor is composed of two chains, interleukin-28R/likely interleukin or cytokine or receptor 2 (IL-28R/LICR2) and IL-10R beta, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-lambda 1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs. We used IL-28R/LICR2-mutated receptors to identify the tyrosines required for STAT activation, as well as antiproliferative and antiviral activities. We found that IFN-lambda 1-induced STAT2 tyrosine phosphorylation is mediated through tyrosines 343 and 517 of the receptor, which showed some similarities with tyrosines from type I IFN receptors involved in STAT2 activation. These two tyrosines were also responsible for antiviral and antiproliferative activities of IFN-lambda 1. By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues. Taken together, these observations extend the functional similarities between IFN-lambdas and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.
20: The Journal of biological chemistry, 2004 Jul 30, 279(31)
Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling.
[Abstract]Interferon (IFN)-lambda 1, -lambda 2, and -lambda 3 are the latest members of the class II cytokine family and were shown to have antiviral activity. Their receptor is composed of two chains, interleukin-28R/likely interleukin or cytokine or receptor 2 (IL-28R/LICR2) and IL-10R beta, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-lambda 1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs. We used IL-28R/LICR2-mutated receptors to identify the tyrosines required for STAT activation, as well as antiproliferative and antiviral activities. We found that IFN-lambda 1-induced STAT2 tyrosine phosphorylation is mediated through tyrosines 343 and 517 of the receptor, which showed some similarities with tyrosines from type I IFN receptors involved in STAT2 activation. These two tyrosines were also responsible for antiviral and antiproliferative activities of IFN-lambda 1. By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues. Taken together, these observations extend the functional similarities between IFN-lambdas and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.