Identification of a Peptide Derived from Vaccinia Virus A52R Protein That Inhibits Cytokine Secretion in Response to TLR-Dependent Signaling and Reduces In Vivo Bacterial-Induced Inflammation

McCoy, Sharon L.; Kurtz, Stephen E.; MacArthur, Carol J.; Trune, Dennis R.; Hefeneider, Steven H.

doi:10.4049/jimmunol.174.5.3006

Cited by 52 publications

(43 citation statements)

References 45 publications

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“…Recent studies have indicated that the requisite TRAF6-dependent induction of NF-B following TLR ligation can be inhibited by the viral vaccinia A52R protein (29,31). For these experiments, a cellpermeable peptide fragment containing a biologically active 11-aa motif from the A52R protein (DIVK) was engineered as described (28) and used to test the dependence of sVSG signaling on TRAF6 activation.…”

Section: Inhibition Of Tlr Signaling Results In Augmented Ib␣ Degradamentioning

confidence: 99%

“…Down-regulation of TLR receptor signaling by peptide-mediated inhibition of TRAF6 activity has been previously established in RAW 264.7 macrophages using a specific 11-aa sequence derived from the vaccinia A52R protein (28,29). A 9-aa polyarginine tail was added to the C-terminal end of the A52R sequence to promote cell membrane permeability of the peptide.…”

Section: Peptide Inhibition Of Tlr Signalingmentioning

confidence: 99%

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The Soluble Variant Surface Glycoprotein of African Trypanosomes Is Recognized by a Macrophage Scavenger Receptor and Induces IκBα Degradation Independently of TRAF6-Mediated TLR Signaling

Leppert

Mansfield

Paulnock

2007

The Journal of Immunology

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The GPI residues of soluble variant surface glycoprotein (sVSG) molecules released from the membrane of African trypanosomes during infection induce macrophage activation events. In this study, we demonstrate that the trypanosome sVSG molecule binds to the membrane of murine RAW 264.7 macrophages and activates the NF-κB cascade independently of a TLR-mediated interaction. The binding of fluorochrome-labeled sVSG molecules to macrophage membranes was saturable, was inhibited by the scavenger receptor-specific ligand maleylated BSA, and was followed by rapid intracellular uptake of the molecules and subsequent internalization to lysosomal compartments. Inhibition of cellular phagocytic and endocytic uptake processes by cytochalasin B and monodansylcadaverine, respectively, revealed that sVSG internalization was necessary for IκBα degradation and occurred by an actin-dependent, clathrin-independent process. Activation of RAW 264.7 cells by sVSG following treatment of the cells with the TRAF6 inhibitory peptide DIVK resulted in enhanced NF-κB signaling, suggesting both that TRAF6-dependent TLR activation of the pathway alone is not required for signaling and that TLR pathway components may negatively regulate expression of sVSG-induced signaling. These results demonstrate that stimulation of macrophages by sVSG involves a complex process of receptor-mediated binding and uptake steps, leading to both positive and negative signaling events that ultimately regulate cellular activation.

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Section: Inhibition Of Tlr Signaling Results In Augmented Ib␣ Degradamentioning

confidence: 99%

Section: Peptide Inhibition Of Tlr Signalingmentioning

confidence: 99%

The Soluble Variant Surface Glycoprotein of African Trypanosomes Is Recognized by a Macrophage Scavenger Receptor and Induces IκBα Degradation Independently of TRAF6-Mediated TLR Signaling

Leppert

Mansfield

Paulnock

2007

The Journal of Immunology

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“…A cyclohexene derivative, TAK-242, prevents TLR4 activation and was found to reduce the cytokine response to endotoxemic shock in mice (121,122). The Vaccinia virus protein A52R also reduces the TLR-mediated response by interacting with IRAK2 and TRAF6, and was found to reduce the cytokine response in an animal model of infectious otitis media (123,124) and to increase survival in models of endotoxemia (125).…”

Section: Therapeutic Manipulation Of Tlr Signaling In the Setting Of mentioning

confidence: 99%

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Gribar

Richardson

Sodhi

et al. 2008

Mol Med

142

109

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Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.

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“…Depletion of IB␣ allows NF-B to enter the nucleus and turn on transcription of proinflammatory genes. Whereas poxviruses are known to encode proteins that inhibit intracellular signaling events involving NF-B (6,12,22,35,39,44,46), there has been no report to date of such a role for E3L. Therefore, we queried whether infection with the ⌬E3L virus activates the NF-B pathway, as reflected by a change in the steady-state level of IB␣.…”

Section: Fig 4 Effects Of Vaccinia Virus Infection On Constitutive mentioning

confidence: 99%

Vaccinia Virus Infection Attenuates Innate Immune Responses and Antigen Presentation by Epidermal Dendritic Cells

Deng

Dai

Ding

et al. 2006

J Virol

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Langerhans cells (LCs) are antigen-presenting cells in the skin that play sentinel roles in host immune defense by secreting proinflammatory molecules and activating T cells. Here we studied the interaction of vaccinia virus with XS52 cells, a murine epidermis-derived dendritic cell line that serves as a surrogate model for LCs. We found that vaccinia virus productively infects XS52 cells, yet this infection displays an atypical response to anti-poxvirus agents. Whereas adenosine N1-oxide blocked virus production and viral protein synthesis during a synchronous infection, cytosine arabinoside had no effect at concentrations sufficient to prevent virus replication in BSC40 monkey kidney cells. Poxviruses are dermatotropic DNA viruses that cause human diseases ranging in severity from a mild local skin eruption (molluscum contagiosum) to a catastrophic systemic illness signaled by a generalized pustular rash (smallpox). Poxviruses employ multiple strategies to evade the immune system, including (i) secretion of virus-encoded soluble cytokine receptors or cytokine analogs that act as molecular decoys to block the activity of host cytokines and (ii) elaboration of viral antagonists of the major intracellular signaling pathways that either trigger apoptosis, establish an antiviral state, or activate proinflammatory responses (reviewed in reference 44). Vaccinia virus, the laboratory prototype for the poxvirus family, has a 200-year history of intentional human infection via the skin for the purpose of smallpox prophylaxis. The stigma of successful vaccination is a localized pustular rash that, in uncomplicated cases, heals without either spreading to adjacent areas of skin or triggering serious systemic inflammation. Major complications of vaccination such as eczema vaccinatum are more common in individuals with abnormal skin immunity (50). Life-threatening progressive vaccinia virus occurs in patients with T-cell immunodeficiency (18). Molluscum contagiosum, a normally benign and self-limited skin infection of healthy children, is either more severe or more difficult to eradicate in children with atopic dermatitis and in immunocompromised patients (13,17). These clinical correlations suggest that delineating the biology of natural poxvirus infections and the mechanisms underlying immunization via scarification (and ways to avoid or treat the complications of vaccination) would benefit from a better understanding of the interactions of poxviruses with the skin immune system.Langerhans cells (LCs) are epidermal antigen-presenting dendritic cells (DCs) that play important roles in skin immune responses (3,40). Derived from CD34 ϩ progenitor cells in the bone marrow (28), they establish their residence in the basal and suprabasal layers of the epidermis. Whereas LCs in noninflamed skin are maintained by skin-resident hematopoietic precursors that self-renew in situ, skin injury results in loss of resident LCs and their replacement by circulating monocyte precursors (19,36). LCs in the epidermis are immature, though capa...

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Identification of a Peptide Derived from Vaccinia Virus A52R Protein That Inhibits Cytokine Secretion in Response to TLR-Dependent Signaling and Reduces In Vivo Bacterial-Induced Inflammation

Cited by 52 publications

References 45 publications

The Soluble Variant Surface Glycoprotein of African Trypanosomes Is Recognized by a Macrophage Scavenger Receptor and Induces IκBα Degradation Independently of TRAF6-Mediated TLR Signaling

The Soluble Variant Surface Glycoprotein of African Trypanosomes Is Recognized by a Macrophage Scavenger Receptor and Induces IκBα Degradation Independently of TRAF6-Mediated TLR Signaling

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Vaccinia Virus Infection Attenuates Innate Immune Responses and Antigen Presentation by Epidermal Dendritic Cells

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