Raymond P Donnelly

Publications (30)187.24 Total impact

• Article: Interferon-lambda (IFN-λ) induces signal transduction and gene expression in human hepatocytes but not in lymphocytes or monocytes.

  Harold Dickensheets, Faruk Sheikh, Ogyi Park, Bin Gao, Raymond P Donnelly
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  ABSTRACT: This study compared the ability of IFN-α and IFN-λ to induce signal transduction and gene expression in primary human hepatocytes, PBLs, and monocytes. IFN-α drug products are widely used to treat chronic HCV infection; however, IFN-α therapy often induces hematologic toxicities as a result of the broad expression of IFNARs on many cell types, including most leukocytes. rIFN-λ1 is currently being tested as a potential alternative to IFN-α for treating chronic HCV. Although IFN-λ has been shown to be active on hepatoma cell lines, such as HepG2 and Huh-7, its ability to induce responses in primary human hepatocytes or leukocytes has not been examined. We found that IFN-λ induces activation of Jak/STAT signaling in mouse and human hepatocytes, and the ability of IFN-λ to induce STAT activation correlates with induction of numerous ISGs. Although the magnitude of ISG expression induced by IFN-λ in hepatocytes was generally lower than that induced by IFN-α, the repertoire of regulated genes was quite similar. Our findings demonstrate that although IFN-α and IFN-λ signal through distinct receptors, they induce expression of a common set of ISGs in hepatocytes. However, unlike IFN-α, IFN-λ did not induce STAT activation or ISG expression by purified lymphocytes or monocytes. This important functional difference may provide a clinical advantage for IFN-λ as a treatment for chronic HCV infection, as it is less likely to induce the leukopenias that are often associated with IFN-α therapy.
  Journal of leukocyte biology 12/2012; · 4.99 Impact Factor
• Article: Type III IFNs Are Produced by and Stimulate Human Plasmacytoid Dendritic Cells.

  Zhiwei Yin, Jihong Dai, Jing Deng, Faruk Sheikh, Mahwish Natalia, Tiffany Shih, Anita Lewis-Antes, Sheela B Amrute, Ursula Garrigues, Sean Doyle, Raymond P Donnelly, Sergei V Kotenko, Patricia Fitzgerald-Bocarsly
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  ABSTRACT: Plasmacytoid dendritic cells (pDC) are rare cells found in peripheral blood and lymphoid tissues. pDC are considered to be "professional" type I IFN-producing cells and produce 10- to 100-fold more IFN-α than other cell types in response to enveloped viruses or synthetic TLR7 and TLR9 agonists. In this study, purified pDC were found to express high levels of IFN-λ receptor mRNA, as well as cell-surface IFN-λ receptor. We have developed intracellular flow cytometry assays using Abs to IFN-λ1/3 or -λ2 to assess the expression of IFN-λ proteins by pDC. We observed that a subset of human pDC expresses only intracellular IFN-α, whereas another subset produces both IFN-α and IFN-λ after stimulation with virus or the TLR9 agonist, CpG A; the cells that coexpressed IFN-α and IFN-λ were the cells with the highest levels of IFN-α expression. Ab cross-linking of CD4 or CD303 molecules on pDC inhibited both HSV-induced IFN-λ and IFN-α production. Like the production of IFN-α, the HSV-induced IFN-λ production in pDC was mediated through TLR9 and independent of virus replication. Exogenous IFN-λ treatment of pDC resulted in increased virus-induced expression of both IFN-α and IFN-λ. In addition, both exogenous IFN-λ and -α inhibited dexamethasone-induced apoptosis of pDC. We conclude that pDC are major producers of IFN-λ1 and -λ2 in response to viral stimulation and also express functional receptors for this cytokine. Thus, IFN-λ can serve as an autocrine signal to strengthen the antiviral response of pDC by increasing IFN-α and IFN-λ production, resulting in prolonged pDC survival.
  The Journal of Immunology 08/2012; 189(6):2735-45. · 5.79 Impact Factor
• Source

  Available from: Achsah D Keegan

  Article: IL-4 engagement of the type I IL-4 receptor complex enhances mouse eosinophil migration to eotaxin-1 in vitro.

  Nicola M Heller, William M Gwinn, Raymond P Donnelly, Stephanie L Constant, Achsah D Keegan
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  ABSTRACT: Previous work from our laboratory demonstrated that IL-4Rα expression on a myeloid cell type was responsible for enhancement of Th2-driven eosinophilic inflammation in a mouse model of allergic lung inflammation. Subsequently, we have shown that IL-4 signaling through type I IL-4 receptors on monocytes/macrophages strongly induced activation of the IRS-2 pathway and a subset of genes characteristic of alternatively activated macrophages. The direct effect(s) of IL-4 and IL-13 on mouse eosinophils are not clear. The goal of this study was determine the effect of IL-4 and IL-13 on mouse eosinophil function. Standard Transwell chemotaxis assay was used to assay migration of mouse eosinophils and signal transduction was assessed by Western blotting. Here we determined that (i) mouse eosinophils express both type I and type II IL-4 receptors, (ii) in contrast to human eosinophils, mouse eosinophils do not chemotax to IL-4 or IL-13 although (iii) pre-treatment with IL-4 but not IL-13 enhanced migration to eotaxin-1. This IL-4-mediated enhancement was dependent on type I IL-4 receptor expression: γC-deficient eosinophils did not show enhancement of migratory capacity when pre-treated with IL-4. In addition, mouse eosinophils responded to IL-4 with the robust tyrosine phosphorylation of STAT6 and IRS-2, while IL-13-induced responses were considerably weaker. The presence of IL-4 in combination with eotaxin-1 in the allergic inflammatory milieu could potentiate infiltration of eosinophils into the lungs. Therapies that block IL-4 and chemokine receptors on eosinophils might be more effective clinically in reducing eosinophilic lung inflammation.
  PLoS ONE 01/2012; 7(6):e39673. · 4.09 Impact Factor
• Article: Interferon-lambda and therapy for chronic hepatitis C virus infection.

  Raymond P Donnelly, Harold Dickensheets, Thomas R O'Brien
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  ABSTRACT: Interferon (IFN)-α, a type-I IFN, is widely used to treat chronic hepatitis C virus infection, but the broad expression of IFN-α receptors often leads to adverse reactions in many organs. Here, we examine IFN-λ, a type-III IFN, as a therapeutic alternative to IFN-α. Like IFN-α, IFN-λ also induces antiviral activity in hepatocytes, but might induce fewer adverse reactions because its receptor is largely restricted to cells of epithelial origin. We also discuss the recent discovery of single nucleotide polymorphisms (SNPs) near the human IFN-λ3 gene, IL28B, that correlate strongly with the ability to achieve a sustained virological response to therapy with pegylated IFN-α plus ribavirin in patients with chronic hepatitis C.
  Trends in Immunology 08/2011; 32(9):443-50. · 10.40 Impact Factor
• Article: A novel role for IL-22R1 as a driver of inflammation.

  Ram Savan, Adelle P McFarland, Della A Reynolds, Lionel Feigenbaum, Karthika Ramakrishnan, Megan Karwan, Hidekazu Shirota, Dennis M Klinman, Kieron Dunleavy, Stefania Pittaluga, Stephen K Anderson, Raymond P Donnelly, Wyndham H Wilson, Howard A Young
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  ABSTRACT: The interleukin (IL)-22R1 chain of the heterodimeric IL-22 receptor is not expressed on normal leukocytes, but this receptor is expressed on T cells from anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large cell lymphoma (ALCL) patients. To investigate the consequences of aberrant expression of this receptor on lymphocytes, we generated transgenic mice that express IL-22R1 on lymphocytes. The health of these animals progressively deteriorated at 8 to 12 weeks of age, as they displayed respiratory distress, rough coat and sluggish movement, and subsequent lethality due to multiorgan inflammation. The IL-22R1 transgenic animals developed neutrophilia that correlated with increased levels of circulating IL-17 and granulocyte colony-stimulating factor. In addition, these mice had increased serum IL-22 levels, suggesting that T cells expressing IL-22R1 generate IL-22 in a positive autoregulatory loop. As a result of the mouse model findings, we analyzed circulating cytokine levels in ALK(+)ALCL patients and detected elevated levels of IL-22, IL-17, and IL-8 in untreated patient samples. Importantly, IL-22 and IL-17 were undetectable in all patients who were in complete remission after chemotherapy. This study documents a previously unknown role of IL-22R1 in inflammation and identifies the involvement of IL-22R1/IL-22 in ALK(+)ALCL.
  Blood 10/2010; 117(2):575-84. · 9.90 Impact Factor
• Article: Interleukin-26: an IL-10-related cytokine produced by Th17 cells.

  Raymond P Donnelly, Faruk Sheikh, Harold Dickensheets, Ram Savan, Howard A Young, Mark R Walter
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  ABSTRACT: IL-26 is classified as a member of the IL-10 cytokine family because it has limited sequence homology to IL-10 and the IL-10-related cytokines. The human IL-26 gene, IL26, is located on chromosome 12q15 between the genes for two other important class-2 cytokines, IFNG (IFN-γ) and IL22 (IL-22). IL-26 is often co-expressed with IL-22 by activated T cells, especially Th17 cells. It signals through a heterodimeric receptor complex composed of the IL-20R1 and IL-10R2 chains. IL-26 receptors are primarily expressed on non-hematopoietic cell types, particularly epithelial cells. Signaling through IL-26 receptor complexes results in the activation of STAT1 and STAT3 with subsequent induction of IL-26-responsive genes. The biological functions of IL-26 have only begun to be defined.
  Cytokine & growth factor reviews 10/2010; 21(5):393-401. · 6.49 Impact Factor
• Article: Interferon-lambda: a new addition to an old family.

  Raymond P Donnelly, Sergei V Kotenko
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  ABSTRACT: The discovery and initial description of the interferon-lambda (IFN-lambda) family in early 2003 opened an exciting new chapter in the field of IFN research. There are 3 IFN-lambda genes that encode 3 distinct but highly related proteins denoted IFN-lambda1, -lambda2, and -lambda3. These proteins are also known as interleukin-29 (IL-29), IL-28A, and IL-28B, respectively. Collectively, these 3 cytokines comprise the type III subset of IFNs. They are distinct from both type I and type II IFNs for a number of reasons, including the fact that they signal through a heterodimeric receptor complex that is different from the receptors used by type I or type II IFNs. Although type I IFNs (IFN-alpha/beta) and type III IFNs (IFN-lambda) signal via distinct receptor complexes, they activate the same intracellular signaling pathway and many of the same biological activities, including antiviral activity, in a wide variety of target cells. Consistent with their antiviral activity, expression of the IFN-lambda genes and their corresponding proteins is inducible by infection with many types of viruses. Therefore, expression of the type III IFNs (IFN-lambdas) and their primary biological activity are very similar to the type I IFNs. However, unlike IFN-alpha receptors which are broadly expressed on most cell types, including leukocytes, IFN-lambda receptors are largely restricted to cells of epithelial origin. The potential clinical importance of IFN-lambda as a novel antiviral therapeutic agent is already apparent. In addition, preclinical studies by several groups indicate that IFN-lambda may also be useful as a potential therapeutic agent for other clinical indications, including certain types of cancer.
  Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 08/2010; 30(8):555-64. · 1.63 Impact Factor
• Article: Resistance to IFN-alpha-induced apoptosis is linked to a loss of STAT2.

  Ana L Romero-Weaver, Hsiang-Wen Wang, Håkan C Steen, Anthony J Scarzello, Veronica L Hall, Faruk Sheikh, Raymond P Donnelly, Ana M Gamero
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  ABSTRACT: Type I IFNs (IFN-alpha/beta) are pleitropic cytokines widely used in the treatment of certain malignancies, hepatitis B and C, and multiple sclerosis. IFN resistance is a challenging clinical problem to overcome. Hence, understanding the molecular mechanism by which IFN immunotherapy ceases to be effective is of translational importance. In this study, we report that continuous IFN-alpha stimulation of the human Jurkat variant H123 led to resistance to type I IFN-induced apoptosis due to a loss of signal transducers and activators of transcription 2 (STAT2) expression. The apoptotic effects of IFN-alpha were hampered as STAT2-deficient cells were defective in activating the mitochondrial-dependent death pathway and ISGF3-mediated gene activation. Reconstitution of STAT2 restored the apoptotic effects of IFN-alpha as measured by the loss of mitochondrial membrane potential, cytochrome c release from mitochondria, caspase activation, and ultimately cell death. Nuclear localization of STAT2 was a critical event as retention of tyrosine-phosphorylated STAT2 in the cytosol was not sufficient to activate apoptosis. Furthermore, silencing STAT2 gene expression in Saos2 and A375S.2 tumor cell lines significantly reduced the apoptotic capacity of IFN-alpha. Altogether, we show that STAT2 is a critical mediator in the activation of type I IFN-induced apoptosis. More importantly, defects in the expression or nuclear localization of STAT2 could lessen the efficacy of type I IFN immunotherapy.
  Molecular Cancer Research 01/2010; 8(1):80-92. · 4.29 Impact Factor
• Article: An overview of cytokines and cytokine antagonists as therapeutic agents.

  Raymond P Donnelly, Howard A Young, Amy S Rosenberg
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  ABSTRACT: Cytokine-based therapies have the potential to provide novel treatments for cancer, autoimmune diseases, and many types of infectious disease. However, to date, the full clinical potential of cytokines as drugs has been limited by a number of factors. To discuss these limitations and explore ways to overcome them, the FDA partnered with the New York Academy of Sciences in March 2009 to host a two-day forum to discuss more effective ways to harness the clinical potential of cytokines and cytokine antagonists as therapeutic agents. The first day was focused primarily on the use of recombinant cytokines as therapeutic agents for treatment of human diseases. The second day focused largely on the use of cytokine antagonists as therapeutic agents for treatment of human diseases. This issue of the Annals includes more than a dozen papers that summarize much of the information that was presented during this very informative two-day conference.
  Annals of the New York Academy of Sciences 12/2009; 1182:1-13. · 3.15 Impact Factor
• Article: IFN-gamma down-regulates Secretoglobin 3A1 gene expression.

  Atsushi Yamada, Dai Suzuki, Agasa Miyazono, Kumiko Oshima, Akihide Kamiya, Baohong Zhao, Masamichi Takami, Raymond P Donnelly, Hiroyuki Itabe, Matsuo Yamamoto, Shioko Kimura, Ryutaro Kamijo
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  ABSTRACT: STAT1 mediates Interferon (IFN)-dependent positive and negative regulation of inflammatory gene expression in lung. In this study, we examined the effect of IFN-gamma on the expression of SCGB3A1 which is thought to play crucial roles in inflammation and epithelial cell differentiation in lung. We found that expression of SCGB3A1 was down-regulated by IFN-gamma in a time- and dose-dependent manner in the murine transformed Clara Cells (mtCC) line. IFN-gamma induced the phosphorylation of STAT1, which binds to a STAT-binding element (SBE) in the SCGB3A1 gene promoter, leading to decreased transcriptional activation of this gene.
  Biochemical and Biophysical Research Communications 02/2009; 379(4):964-8. · 2.48 Impact Factor
• Source

  Available from: PubMed Central

  Article: Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity.

  Ilkka S Junttila, Kiyoshi Mizukami, Harold Dickensheets, Martin Meier-Schellersheim, Hidehiro Yamane, Raymond P Donnelly, William E Paul
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  ABSTRACT: Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow-derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional gammac made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of gammac had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac accounted for the distinct IL-4-IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.
  Journal of Experimental Medicine 11/2008; 205(11):2595-608. · 13.85 Impact Factor
• Article: Oncostatin M regulates secretoglobin 3A1 and 3A2 expression in a bidirectional manner.

  Takeshi Tomita, Atsushi Yamada, Masaaki Miyakoshi, Taketomo Kido, Faruk Sheikh, Achara Srisodsai, Atsushi Miyajima, Raymond P Donnelly, Shioko Kimura
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  ABSTRACT: Secretoglobin (SCGB) 3A1 and 3A2 are members of the small molecular weight secretoglobin gene superfamily. SCGB3A1 is a tumor suppressor gene, whereas SCGB3A2 has anti-inflammatory properties. Both genes are mainly expressed in the lung and trachea in mice. Whether the expression and/or function of these two genes are related is not known. Here we show that the expression of SCGB3A1 and SCGB3A2 are bidirectionally regulated by oncostatin M (OSM) when examined in a mouse transformed Clara cell line (mtCC); SCGB3A1 is up-regulated by OSM, while SCGB3A2 is down-regulated in a time- and dose-dependent manner. OSM-activated STAT3/5, through binding to the STAT-binding element located at -201 to -209 bp in the mouse Scgb3a1 gene promoter, and the extracellular signal-regulated kinase (ERK)- and p38-mitogen-activated protein kinase (MAPK) pathways are responsible for the OSM-induced up-regulation of SCGB3A1 expression. On the other hand, the -113 to -273 bp region in the Scgb3a2 promoter appears to be responsible for the OSM induced down-regulation of the gene. No significant differences in the levels or patterns of specific DNA-binding proteins were found in the -113 to -273 bp region as determined by electrophoretic mobility shift assays. Neither the ERK- nor p38-MAPK pathways were involved in the OSM-induced reduction of Scgb3a2 promoter activity. These results suggest that OSM-induced suppression of SCGB3A2 expression is an indirect effect of OSM. Expression of the Clara cell marker, CYP2F2, was markedly decreased upon OSM treatment in parallel with the decrease of SCGB3A2 expression in mtCC cells. The differential regulation of Scgb3a1 and Scgb3a2 gene expression by OSM may explain the unique functions of these genes in the lung.
  American Journal of Respiratory Cell and Molecular Biology 11/2008; 40(5):620-30. · 5.13 Impact Factor
• Article: IFN-alpha and IFN-lambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity.

  Stephen G Maher, Faruk Sheikh, Anthony J Scarzello, Ana L Romero-Weaver, Darren P Baker, Raymond P Donnelly, Ana M Gamero
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  ABSTRACT: Interferon (IFN)-lambda, also known as IL-28A, IL-28B or IL-29, is a new type III IFN, which like type I IFN-(alpha/beta), activates common elements of the JAK/STAT signaling pathway and exhibits antiproliferative activity. Currently, IFN-alpha is used in the treatment of certain forms of cancer, but its antitumor effects are limited and associated with high toxicity. In this study, we determined whether IFN-lambda induced the same level of cell growth inhibition relative to IFN-alpha. To this effect HaCaT cells, which are typically growth inhibited by IFN-alpha, underwent apoptosis in response to IFN-lambda. Next, in contrast to IFN-alpha stimulation, IFN-lambda prolonged the duration of activated STAT1 and STAT2. Furthermore, the kinetics of IFN-stimulated genes was different as IFN-lambda induced a delayed but stronger induction of IFN-responsive genes. Components of the JAK/STAT pathway remained essential for the antiproliferative effects of IFN-alpha and IFN-lambda. IFN-lambda-induced persistence of STAT activation required de novo protein synthesis and was in part due to a delay in STAT2 inactivation. Thus our data demonstrate that the duration of IFN-lambda signaling is different from that of IFN-alpha, and that IFN-lambda could be a suitable cytokine to evaluate for cancer therapy.
  Cancer biology & therapy 08/2008; 7(7):nihpa47781. · 2.64 Impact Factor
• Article: Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain.

  Thirumalai R Ramalingam, John T Pesce, Faruk Sheikh, Allen W Cheever, Margaret M Mentink-Kane, Mark S Wilson, Sean Stevens, David M Valenzuela, Andrew J Murphy, George D Yancopoulos, Joseph F Urban, Raymond P Donnelly, Thomas A Wynn
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  ABSTRACT: The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (T(H)2)-mediated disease and associates with either the common gamma-chain to form the type I IL-4R or with the IL-13R alpha1 chain (IL-13Ralpha1) to form the type II IL-4R. Here we used Il13ra1-/- mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra-/- mice, which have weak T(H)2 responses, Il13ra1-/- mice had exacerbated T(H)2 responses. Il13ra1-/- mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13Ralpha1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses.
  Nature Immunology 02/2008; 9(1):25-33. · 26.01 Impact Factor
• Source

  Available from: Ana M Gamero

  Article: A Mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type I IFN-induced apoptosis.

  Anthony J Scarzello, Ana L Romero-Weaver, Stephen G Maher, Timothy D Veenstra, Ming Zhou, Angel Qin, Raymond P Donnelly, Faruk Sheikh, Ana M Gamero
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  ABSTRACT: Type I interferons (IFN-alpha/beta) induce apoptosis in certain tumor cell lines but not others. Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I IFNs. This mutation was introduced in a conserved motif, PYTK, located in the STAT SH2 domain, which is shared by STAT1, STAT2, and STAT3. To test whether the tyrosine in this motif might be phosphorylated and affect signaling, Y631 of STAT2 was mutated to phenylalanine (Y631F). Although it was determined that Y631 was not phosphorylated, the Y631F mutation conferred sustained signaling and induction of IFN-stimulated genes. This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP. Finally, cells bearing the Y631F mutation in STAT2 underwent apoptosis after IFN-alpha stimulation compared with wild-type STAT2. Therefore, this mutation reveals that a prolonged response to IFN-alpha could account for one difference between tumor cell lines that undergo IFN-alpha-induced apoptosis compared with those that display an antiproliferative response but do not die.
  Molecular Biology of the Cell 08/2007; 18(7):2455-62. · 4.94 Impact Factor
• Article: Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex.

  Sung Il Yoon, Naomi J Logsdon, Faruk Sheikh, Raymond P Donnelly, Mark R Walter
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  ABSTRACT: Interleukin-10 receptor 2 (IL-10R2) is a critical component of the IL-10.IL-10R1.IL-10R2 complex which regulates IL-10-mediated immunomodulatory responses. The ternary IL-10 signaling complex is assembled in a sequential order with the IL-10.IL-10R1 interaction occurring first followed by engagement of the IL-10R2 chain. In this study we map the IL-10R2 binding site on IL-10 using surface plasmon resonance and cell-based assays. Critical IL-10R2 binding residues are located in helix A adjacent to the previously identified IL-10R1 recognition surface. Interestingly, IL-10R2 binding residues located in the N-terminal end of helix A exhibit large structural differences between unbound cIL-10 and cIL-10.IL-10R1 crystal structures. This suggests IL-10R1-induced conformational changes regulate IL-10R2 binding and assembly of the ternary IL-10.IL-10R1.IL-10R2 complex. The basic mechanistic features of the assembly process are likely shared by six additional class-2 cytokines (viral IL-10s, IL-22, IL-26, IL-28A, IL28B, and IL-29) to promote IL-10R2 binding to six additional receptor complexes. These studies highlight the importance of structure in regulating low affinity protein-protein interactions and IL-10 signal transduction.
  Journal of Biological Chemistry 12/2006; 281(46):35088-96. · 4.77 Impact Factor
• Article: The IFN-λ Family (IL-28/29)

  Sergei V. Kotenko, Raymond P. Donnelly
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  ABSTRACT: IFN-λs or type III IFNs are also known as IL-28/29. This group of cytokines is the latest addition to the family of cytokines that signal through receptors of the class II cytokine receptor family (CRF2). Although IFN-λs and IFN-α/β (type I IFNs) utilize distinct receptor complexes for signaling, type I and type III IFNs activate the same intracellular signaling pathway and many similar biological activities, including the ability to induce antiviral state in cells. Consistent with their antiviral activity, the expression of IFN-λ mRNAs is inducible by viral an infections. Therefore, IFN-λs functionally resemble type I IFNs, supporting their designation as IFNs. However, IFN- λs also share several common features with cytokines of the IL-10 family that includes IL-19, IL-20, IL-22, IL-24 and IL-26. Their genes have a similar intron-exon structure, they share some sequence homology, and most likely they share a similar structural organization. IFN-λs also share a common receptor subunit, IL-10R2, with IL-10, IL- 22 and IL-26. However, the ligand-binding chain, IFN-λR1, is a unique component of the IFN-λ receptor complex. Although the relative importance of the IFN-λs remains to be fully determined, recent experiments demonstrate their strong potential as antiviral and antitumor therapeutics.
  Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Cu rrent Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) 07/2006; 5(3):279-285.
• Chapter: Type III Interferons: The Interferon‐λ Family

  Sergei V. Kotenko, Raymond P. Donnelly
  06/2006: pages 141 - 163; , ISBN: 9783527608201
• Article: Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus.

  Bo Chi, Harold L Dickensheets, Kirsten M Spann, Marc A Alston, Cindy Luongo, Laure Dumoutier, Jiaying Huang, Jean-Christophe Renauld, Sergei V Kotenko, Mario Roederer, Judy A Beeler, Raymond P Donnelly, Peter L Collins, Ronald L Rabin
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  ABSTRACT: The mechanism by which respiratory syncytial virus (RSV) suppresses T-cell proliferation to itself and other antigens is poorly understood. We used monocyte-derived dendritic cells (MDDC) and CD4 T cells and measured [(3)H]thymidine incorporation to determine the factors responsible for RSV-induced T-cell suppression. These two cell types were sufficient for RSV-induced suppression of T-cell proliferation in response to cytomegalovirus or Staphylococcus enterotoxin B. Suppressive activity was transferable with supernatants from RSV-infected MDDC and was not due to transfer of live virus or RSV F (fusion) protein. Supernatants from RSV-infected MDDC, but not MDDC exposed to UV-killed RSV or mock conditions, contained alpha interferon (IFN-alpha; median, 43 pg/ml) and IFN-lambda (approximately 1 to 20 ng/ml). Neutralization of IFN-alpha with monoclonal antibody (MAb) against one of its receptor chains, IFNAR2, or of IFN-lambda with MAb against either of its receptor chains, IFN-lambdaR1 (interleukin 28R [IL-28R]) or IL-10R2, had a modest effect. In contrast, blocking the two receptors together markedly reduced or completely blocked the RSV-induced suppression of CD4 T-cell proliferation. Defining the mechanism of RSV-induced suppression may guide vaccine design and provide insight into previously uncharacterized human T-cell responses and activities of interferons.
  Journal of Virology 06/2006; 80(10):5032-40. · 5.40 Impact Factor
• Article: Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma.

  Ahmed Lasfar, Anita Lewis-Antes, Sergey V Smirnov, Shubha Anantha, Walid Abushahba, Bin Tian, Kenneth Reuhl, Harold Dickensheets, Faruk Sheikh, Raymond P Donnelly, Elizabeth Raveche, Sergei V Kotenko
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  ABSTRACT: Recently discovered type III IFNs (IFN-lambda) exert their antiviral and immunomodulatory activities through a unique receptor complex composed of IFN-lambdaR1 and interleukin-10 receptor 2. To further study type III IFNs, we cloned and characterized mouse IFN-lambda ligand-receptor system. We showed that, similar to their human orthologues, mIFN-lambda2 and mIFN-lambda3 signal through the IFN-lambda 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-lambdas. We developed B16 cells constitutively expressing murine IFN-lambda2 (B16.IFN-lambda2 cells) and evaluated their tumorigenicity in syngeneic C57BL/6 mice. Although constitutive expression of mIFN-lambda2 in melanoma cells did not affect their proliferation in vitro, the growth of B16.IFN-lambda2 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-lambda2 expression. We then developed IFN-lambda-resistant B16.IFN-lambda2 cells (B16.IFN-lambda2Res cells) and showed that their tumorigenicity was also highly impaired or completely abolished similar to B16.IFN-lambda2 cells, suggesting that IFN-lambdas engage host mechanisms to inhibit melanoma growth. These in vivo experiments show the antitumor activities of IFN-lambdas and suggest their strong therapeutic potential.
  Cancer Research 05/2006; 66(8):4468-77. · 7.86 Impact Factor