Enhancement of Antiviral Immunity by Small Molecule Antagonist of Suppressor of Cytokine Signaling

Ahmed, Chulbul M.; Dabelic, Rea; Martin, James P.; Jager, Lindsey D.; Haider, Shozeb; Johnson, Howard M.

doi:10.4049/jimmunol.0902895

Cited by 34 publications

(53 citation statements)

References 44 publications

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“…These data indicate that pJAK2 is sufficient to attenuate SOCS1 function, thereby allowing either endogenous or exogenous JAK/STAT signaling pathways to exert their antiviral effects, and to promote keratinocyte survival. In a similar manner, pretreatment of mice with pJAK2 also provides protection against lethal vaccinia and encephalomyocarditis virus infections (1). While these examples are limited and preliminary, they suggest that manipulation of SOCS proteins is possible during viral infection and may provide a potent mechanism for inhibiting viral replication.…”

Section: Effects Of Socs Expression On Viral Diseasementioning

confidence: 88%

“…The KIR is thought to function as a pseudosubstrate to inhibit the kinase activity of proteins that are bound by, or in close proximity to, the SOCS protein. (1), which leads to the recruitment of cytoplasmic STAT proteins (2). Recruited STATs are activated by JAK phosphorylation (3), allowing them to dimerize (4) and enter the nucleus as a transcription factor complex to induce the expression of target genes.…”

Section: Socs Protein Structure and Functionmentioning

confidence: 99%

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Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

111

102

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Over the past decade, a family of host proteins known as suppressors of cytokine signaling (SOCS) have emerged as frequent targets of viral exploitation. Under physiologic circumstances, SOCS proteins negatively regulate inflammatory signaling pathways by facilitating ubiquitination and proteosomal degradation of pathway machinery. Their expression is tightly regulated to prevent excessive inflammation while maintaining protective antipathogenic responses. Numerous viruses, however, have developed mechanisms to induce robust host SOCS protein expression following infection, essentially "hijacking" SOCS function to promote virus survival. To date, SOCS proteins have been shown to inhibit protective antiviral signaling pathways, allowing viruses to evade the host immune response, and to ubiquitinate viral proteins, facilitating intracellular viral trafficking and progeny virus assembly. Importantly, manipulation of SOCS proteins not only facilitates progression of the viral life cycle but also powerfully shapes the presentation of viral disease. SOCS proteins can define host susceptibility to infection, contribute to peripheral disease manifestations such as immune dysfunction and cancer, and even modify the efficacy of therapeutic interventions. Looking toward the future, it is clear that a better understanding of the role of SOCS proteins in viral diseases will be essential in our struggle to modulate and even eliminate the pathogenic effects of viruses on the host.

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Section: Effects Of Socs Expression On Viral Diseasementioning

confidence: 88%

Section: Socs Protein Structure and Functionmentioning

confidence: 99%

Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

111

102

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“…Fourth, pJAK2(1001-1013) enhanced antigen-specific splenocyte proliferation (23). Subsequently, pJAK2(1001-1013) was reported to enhance antiviral immunity (24). In this study, the SOCS1 antagonist pJAK2(1001-1013) peptide upregulated the expression of the maturation marker (CD83) and costimulatory molecule (CD86) of RNAelectroporated mDCs, potentiated the capacity of mDCs to induce T-cell proliferation, stimulated the secretion of proinflammatory cytokine IL-12, and enhanced the cytotoxicity of tumor cell antigen-specific CTLs activated by human gastric cancer cell total RNA-electroporated mDCs.…”

Section: Discussionmentioning

confidence: 99%

“…The lipo-pJAK2(1001-1013) and lipo-JAK2(1001-1013)2A peptides were characterized by mass spectrometry and purified by high-performance liquid chromatography. Peptides were dissolved in water or dimethyl sulfoxide (Sigma-Aldrich) (24).…”

Section: Rna Extraction Human Gastric Cancer Mgc-803 Cells (Cancer Rmentioning

confidence: 99%

“…Research results demonstrated that the pJAK2(1001-1013) peptide can block SOCS1-induced inhibition of STAT3 phosphorylation in IL-6-treated prostate cancer cells and enhance antigen-specific splenocyte proliferation (23). Later, they reported that, in addition to a direct antiviral effect and synergism with IFN-␥, the pJAK2(1001-1013) peptide exhibits adjuvant effects on humoral and cellular immunity, as well as an enhancement of polyinosinic-poly(C) activation of Toll-like receptor 3 (TLR3) (24). However, the effect of the SOCS1 antagonist pJAK2(1001-1013) peptide on DCs is still unknown.…”

mentioning

confidence: 99%

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A Suppressor of Cytokine Signaling 1 Antagonist Enhances Antigen-Presenting Capacity and Tumor Cell Antigen-Specific Cytotoxic T Lymphocyte Responses by Human Monocyte-Derived Dendritic Cells

Wang

Yuan

et al. 2013

Clin Vaccine Immunol

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The suppressor of cytokine signaling 1 (SOCS1) has emerged as a critical inhibitory molecule for controlling the cytokine response and antigen presentation by dendritic cells (DCs), thereby regulating the magnitude of both innate and adaptive immunity. The aim of this study was to investigate whether the SOCS1 antagonist pJAK2(1001-1013) peptide can weaken or block the inhibition function of SOCS1 in DCs by evaluating the phenotype and cytokine production, antigen-presenting, and specific Tcell-activating capacities of DCs electroporated with human gastric cancer cell total RNA. Furthermore, STAT1 activation of the JAK/STAT signal pathway mediated by SOCS1 was analyzed by Western blotting. The results demonstrate that the SOCS1 antagonist pJAK2(1001-1013) peptide upregulated the expression of the maturation marker (CD83) and costimulatory molecule (CD86) of RNA-electroporated human monocyte-derived mature DCs (mDCs), potentiated the capacity of mDCs to induce Tcell proliferation, stimulated the secretion of proinflammatory cytokines, and enhanced the cytotoxicity of tumor cell antigenspecific CTLs activated by human gastric cancer cell total RNA-electroporated mDCs. Data from Western blot analysis indicate that STAT1 was further activated in pJAK2(1001-1013) peptide-loaded mDCs. These results imply that the SOCS1 antagonist pJAK2(1001-1013) peptide is an effective reagent for the enhancement of antigen-specific antitumor immunity by DCs.

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Therapeutical potential of a peptide mimicking the SOCS1 kinase inhibitory region in skin immune responses

et al. 2013

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IFN-γ-activated keratinocytes are key contributors to the pathogenetic mechanisms leading to type-1 immune-mediated skin disorders. In these epidermal cells, SOCS1 negatively regulates the molecular cascades triggered by IFN-γ by disabling JAK2 phosphorylation through its kinase inhibitory region (KIR). Aimed at potentiating the SOCS1 inhibitory function on JAK2/STAT1 axis in keratinocytes, we recently developed a set of peptides mimicking the SOCS1 KIR domain, which are capable of efficiently binding JAK2 in vitro.Here, the effects of one such SOCS1 KIR mimetic named PS-5 on IFN-γ-activated human keratinocytes were evaluated. We found that IFN-γ-activated keratinocytes treated with PS-5 exhibited impaired JAK2, IFN-γRα, and STAT1 phosphorylation. We also observed reduced levels of the IRF-1 transcription factor, and a strong reduction in ICAM-1, HLA-DR, CXCL10, and CCL2 inflammatory gene expression. ICAM-1 reduced expression resulted in an impaired adhesiveness of T lymphocytes to autologous keratinocytes. Consistently, the migration of T cells toward supernatants from PS-5-treated keratinocytes was drastically reduced. Finally, PS-5 treatment hampered STAT1 activation and the expression of STAT1-dependent inflammatory genes in IFN-γ-treated explants of human skin. These data collectively indicate that PS-5 has an important therapeutic potential in the treatment of type-1 immune-mediated skin diseases.Keywords: Epidermal keratinocytes r IFN-γ-signaling r Skin inflammation r SOCS1 See accompanying Commentary by Kubo IntroductionPathogenetic mechanisms leading to the manifestation of type-1 immune-mediated skin disorders, such as psoriasis and allergic contact dermatitis, are mostly driven by T helper (Th)1 and Th17 lymphocytes, producing massive amounts of IFN-γ and IL-17 plus IFN-γ, respectively [1,2]. In a vast variety of skin diseases, IFN-γ Correspondence: Dr. Cristina Albanesi e-mail: c.albanesi@idi.it is also abundantly released by T cytotoxic (Tc)1 lymphocytes. In addition to IFN-γ and IL-17, type 1 and Th17 cells can release considerable amounts of TNF-α, which in synergy with IFN-γ and IL-17, reinforce the inflammatory responses of target cells, primarily the epidermal keratinocytes [3,4]. Many immune-mediated skin diseases also have involvement by Th22 cells, which affect keratinocyte immune functions by stimulating defined signaling * These authors equally contributed to this work. Eur. J. Immunol. 2013Immunol. . 43: 1883Immunol. -1895 pathways [1]. Despite recent studies demonstrating that IL-17, TNF-α, and IL-22 have a pathogenetic role in the development of psoriasis, IFN-γ remains a pivotal cytokine inducer of resident skin cells in this particular skin disease, as it potently enhances the proinflammatory gene expression in epidermal keratinocytes and alters their apoptotic/growth rate. In this regard, an IFN-γ signature triggered by the Th1-and Tc1-released IFN-γ in psoriatic keratinocytes is responsible for the expression of a stereotyped set of proinflammatory genes, which are activated by th...

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Enhancement of Antiviral Immunity by Small Molecule Antagonist of Suppressor of Cytokine Signaling

Abstract: Material Supplementary 5.DC1http://www.jimmunol.org/content/suppl/2010/06/09/jimmunol.090289

Cited by 34 publications

References 44 publications

Viral Exploitation of Host SOCS Protein Functions

Viral Exploitation of Host SOCS Protein Functions

A Suppressor of Cytokine Signaling 1 Antagonist Enhances Antigen-Presenting Capacity and Tumor Cell Antigen-Specific Cytotoxic T Lymphocyte Responses by Human Monocyte-Derived Dendritic Cells

Therapeutical potential of a peptide mimicking the SOCS1 kinase inhibitory region in skin immune responses

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