Variations in the Unstructured C-terminal Tail of Interferons Contribute to Differential Receptor Binding and Biological Activity

Slutzki, Michal; Jaitin, Diego Adhemar; Yehezkel, Tuval Ben; Schreiber, Gideon

doi:10.1016/j.jmb.2006.05.069

Cited by 54 publications

(82 citation statements)

References 39 publications

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“…No expression of mRNA encoding a cell-associated IFN-lR1 variant with a truncated (23) 100 (46) 0.6 -5 (45)(46)(47)(48)(49) > 0.4 (45,46,48,49) + + + + + + 10 µg/ml À1 IFN-l1 and 500 U ml À1 IFN-b1, which had been preincubated for 2 h with 0, 1 and 10 mg ml À1 sIFNlR1-Fc. Major histocompatibility complex class I (MHC I) cellsurface expression was measured by flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the K D value of 73 nM indicated an approximately 100 times lower binding than that for the interaction of IL-22 with its potently inhibiting soluble receptor IL-22BP, as previously determined by our laboratory. 43 Moreover, the sIFN-lR1-Fc-IFN-l1 binding had a similar (IFN-a1) or lower (IFN-a2, IFN-b) affinity compared with the binding of the extracellular domain of the R1-type IFN receptor subunit IFN-aRB to the respective type I IFN [44][45][46][47][48] ( Figure 7a). Our yet preliminary data also indicated that the affinity of sIFN-lR1-Fc to IFN-l1 was similar to the affinity to IFN-l2.…”

Section: Target Cells Of Type III Interferons K Witte Et Almentioning

confidence: 98%

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Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

et al. 2009

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Interferon (IFN)-l1, -2 and -3 (also designated as interleukin (IL)-29, IL-28a and IL-28b) represent a new subfamily within the class II cytokine family. They show type I IFN-like antiviral and cytostatic activities in affected cells forming the basis for IFN-l1 therapy currently under development for hepatitis C infection. However, many aspects of IFN-ls are still unknown. This study aimed at identifying the target cells of IFN-ls within the immune system and the skin. Among skin cell populations, keratinocytes and melanocytes, but not fibroblasts, endothelial cells or subcutaneous adipocytes turned out to be targets. In contrast to these target cells, blood immune cell populations did not clearly respond to even high concentrations of these cytokines, despite an IFN-l receptor expression. Interestingly, immune cells expressed high levels of a short IFN-l receptor splice variant (sIFN-lR1/sIL-28R1). Its characterization revealed a secreted, glycosylated protein that binds IFN-l1 with a moderate affinity (K D 73 nM) and was able to inhibit IFN-l1 effects. Our study suggests that IFN-l therapy should be suited for patients with verrucae, melanomas and non-melanoma skin cancers, apart from patients with viral hepatitis, and would not be accompanied by immune-mediated complications known from type I IFN application.

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Section: Discussionmentioning

confidence: 99%

Section: Target Cells Of Type III Interferons K Witte Et Almentioning

confidence: 98%

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

et al. 2009

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“…The four single-subtype subclasses (IFN-␣, IFN-␤, IFN-ε, and IFN-) have a COOH-terminal positively charged or hydrophobic tail of 6, 6, 11, and 7 residues, respectively. In the IFN-␣ subclass, this COOHterminal positively charged or hydrophobic tail is thought to contribute to higher antiviral activity in the long isoforms (41).…”

Section: Repertoire and Phylogenic Analysis Of Porcine Type I Ifnsmentioning

confidence: 99%

“…The efficacy of induction of antiviral responses appears different between subclasses and even between subtypes belonging to the same subclass. For example, human IFN-␣ subtypes vary in their ability to activate human natural killer cells, and IFN-␤ shows more potency than IFN-␣2 in inhibition of monocyte proliferation (8,41,43). Therefore, to elucidate the antiviral potency of a type I IFN family, it is essential to systematically analyze their antiviral activity among members of the same and different subclasses.…”

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confidence: 99%

Differential expression and activity of the porcine type I interferon family

Sang¹,

Rowland

Hesse

et al. 2010

Physiological Genomics

193

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Type I interferons (IFNs) are central to innate and adaptive immunity, and many have unique developmental and physiological functions. However, in most species, only two subtypes, IFN-α and IFN-β, have been well studied. Because of the increasing importance of zoonotic viral diseases and the use of pigs to address human research questions, it is important to know the complete repertoire and activity of porcine type I IFNs. Here we show that porcine type I IFNs comprise at least 39 functional genes distributed along draft genomic sequences of chromosomes 1 and 10. These functional IFN genes are classified into 17 IFN-α subtypes, 11 IFN-δ subtypes, 7 IFN-ω subtypes, and single-subtype subclasses of IFN-αω, IFN-β, IFN-ε, and IFN-κ. We found that porcine type I IFNs have diverse expression profiles and antiviral activities against porcine reproductive and respiratory syndrome virus (PRRSV) and vesicular stomatitis virus (VSV), with activity ranging from 0 to >105 U·ng−1·ml−1. Whereas most IFN-α subtypes retained the greatest antiviral activity against both PRRSV and VSV in porcine and MARC-145 cells, some IFN-δ and IFN-ω subtypes, IFN-β, and IFN-αω differed in their antiviral activity based on target cells and viruses. Several IFNs, including IFN-α7/11, IFN-δ2/7, and IFN-ω4, exhibited minimal or no antiviral activity in the tested target cell-virus systems. Thus comparative studies showed that antiviral activity of porcine type I IFNs is virus- and cell-dependent, and IFN-αs are positively correlated with induction of MxA, an IFN-stimulated gene. Collectively, these data provide fundamental genomic information for porcine type I IFNs, information that is necessary for understanding porcine physiological and antiviral responses.

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“…It is recently shown that the binding affi nity of interferon toward IFNAR1 and IFNAR2 receptors correlates with antiviral and antiproliferative effects, (Piehler J et al 2000;Kalie E et al 2007;Slutzki M et al 2006). Human tumor associated macrophages may become tumoricidal under the infl uence of IFN, producing a diffusable substance in agarose culture which causes the antiproliferative effects on tumor cells (Saito T et al 1986).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Utilization of Interferon in Gynecologic and Breast Cancer

Nomelini

Mardegan

Murta

2007

Clinical medicine. Oncology

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Abstract:The usual treatment of gynecologic cancer has been surgery, chemotherapy and radiotherapy. New therapies are being developed to improve efficacy of treatment. Interferons are inducible secretory glycoproteins that have immunomodulatory, antiviral, anti-angiogenic and anti-proliferative effects. Their potential antitumor effect has been demonstrated in many studies. Some patients obtain benefi cial effects; in other patients the treatment failure can occur. IFNs can modulate the immune response and inhibition of tumor angiogenesis. When any alteration in gene expression occurs, there is modulation of the receptors of other cytokines and enzymes that control cell function. These alterations can infl uence the differentiation, cell proliferation rate and apoptosis. The molecular mechanisms that control apoptotic cell death can be improved through cancer management using IFN in single, combination or adjuvant treatment. Malignant cells generally present defects in programmed cell death and apoptosis. Immunomodulation and angiogenesis inhibition are indirect antitumor mechanisms mediated by apoptosis. With regard to immunomodulation, IFNs can have antitumor effects through increases in cytotoxic T cells, natural killer cells and dendritic cells. Angiogenesis inhibition can result from endothelial cell apoptosis. This factor is important in inhibiting tumor genesis and forming metastases. The aim of this review is to discuss the role of Interferon in the treatment of gynecologic malignancies/breast cancer and mechanisms of action.

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Variations in the Unstructured C-terminal Tail of Interferons Contribute to Differential Receptor Binding and Biological Activity

Cited by 54 publications

References 39 publications

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

Differential expression and activity of the porcine type I interferon family

Utilization of Interferon in Gynecologic and Breast Cancer

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