The Oxazolidinone Derivative Locostatin Induces Cytokine Appeasement

Ménoret, Antoine; McAleer, Jeremy P.; Ngoi, Soo-Mun; Ray, Swagatam; Eddy, Nicholas A.; Fenteany, Gabriel; Lee, Seung-Joo; Rossi, Robert J.; Mukherji, Bijay; Allen, David L.; Chakraborty, Nitya G.; Vella, Anthony T.

doi:10.4049/jimmunol.0901414

Cited by 17 publications

(28 citation statements)

References 45 publications

(66 reference statements)

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“…In addition to abating IFNγ production from wild type cells during SIRS (Fig. 5C), locostatin also potently blocks IFNγ and TNFα production upon triggering mouse OT-I or human antigen-specific T cells against influenza with cognate peptide and human PBMCs treated with LPS (50). However, the specificity of this inhibitor is still being investigated as it has several potential off target effects (49).…”

Section: Discussionmentioning

confidence: 99%

RKIP Contributes to IFN-γ Synthesis by CD8+ T Cells after Serial TCR Triggering in Systemic Inflammatory Response Syndrome

Wright

Vella

2013

The Journal of Immunology

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Systemic inflammatory response syndrome (SIRS) is associated with the development of severe medical complications including progression to multiple organ dysfunction syndrome and even death. To date, only marginal improvements in terms of therapeutic options have been established for patients affected by SIRS. Raf kinase inhibitor protein (RKIP) is a regulator of MAPK and NF-κB signaling cascades which are both critical for production of the proinflammatory cytokines responsible for SIRS initiation. By testing a T cell dependent mouse model of SIRS which utilizes staphylococcal enterotoxin A (SEA) specific for Vβ3+ T cells, we show that RKIP is necessary for the exaggerated production of IFNγ from SIRS splenocytes. This effect was not due to differences in T cell expansion, IL-10 production, or APC priming, but rather a cell intrinsic defect lying downstream of the T cell receptor in SEA-specific CD8+ T cells. Importantly, mice lacking RKIP were still able to proliferate, survive, and contribute to cytokine production in response to PAMP-TLR mediated stimuli, despite the TCR-dependent defects seen in our SIRS model. Finally, by blocking RKIP in wild type SIRS splenocytes, the IFNγ response by CD8+ Vβ3+ T cells was significantly diminished. These data suggest that RKIP may be a potential therapeutic target in SIRS by curbing effector cytokine production from CD8+ T cells during serial TCR triggering.

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Section: Discussionmentioning

confidence: 99%

RKIP Contributes to IFN-γ Synthesis by CD8+ T Cells after Serial TCR Triggering in Systemic Inflammatory Response Syndrome

Wright

Vella

2013

The Journal of Immunology

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“…The cells were seeded into 96-well plate at 1 3 10 6 cells/well in 200 mL complete tumor medium for overnight in vitro culture with or without 5 ng mL 21 SIINFEKL stimulation at 37uC and 5% CO 2 , similar to our previous procedure using OT-I cells. 32,33 The supernatant was collected after an overnight culture and the concentration of supernatant interferon-c (IFN-c) and IL-4 was measured using an ELISA Kit (BD Biosciences, San Jose, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Responses to LPS boost effector CD8 T-cell accumulation outside of signals 1 and 2

2015

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Immunization with adjuvant plus antigen induces durable T-cell immunity and is a mainstay of vaccines. Here, the consequence of separating antigen stimulation of T cells from the adjuvant response was studied in a re-transfer model. Effector CD8 T cells in recipient mice were exposed to lipopolysaccharide (LPS), the Toll-like receptor 4 (TLR4) ligand, which significantly increased persistence. While accumulation in lymphoid and non-lymphoid organs was evident, this result depended upon the timing of LPS administration and the presence of the TLR4 adaptor TRIF in the recipient mice. Interestingly, there was very little impact of the LPS response on subset differentiation, which rather appeared to be programmed by antigen and costimulation. To discern factors that limit accumulation, interleukin 10 (IL-10) was targeted since it is a product of TLR4 triggering and mitigates inflammation. Blockade of IL-10 increased accumulation even though the effector CD8 T cells were well past the priming phase, but upon recall interferon-γ secretion was not affected as would be expected when IL-10 is present during priming. Thus, the adjuvant-altered microenvironment is effective not only in the presence of antigen but also during a window of effector CD8 T-cell stasis, suggesting that pathogen-associated molecular pattern molecules released during co-infection, or by vaccines, could alter the survival fate of specific effector T cells.Cellular & Molecular Immunology advance online publication, 20 July 2015; doi:10.1038/cmi.2015.69.

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“…In particular, statins are able to inhibit the mechanism of antigen presentation to T cells and platelet activity, while enhancing nitric oxide production and fibrinolysis [125][126][127]. Locostatin, a Raf kinase inhibitory protein inhibitor, has been found to provoke T cell anergy by blockade of tumor necrosis factor (TNF)-and this last effect was observed in both murine and human lymphocytes [128].…”

Section: Immunotherapeutic Approachesmentioning

confidence: 98%

A Broad Variety of Antigens Contribute to the Pathogenesis of Atherosclerosis: How to Neutralize Noxious Reactions in the Host

Magrone¹,

Jirillo²

2010

EMIDDT

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Atherosclerosis is an inflammatory disease characterized by lipid accumulation as well as vascular injury due to a massive infiltration of immune cells in the endothelial wall. Microbial and self- antigens are responsible for a persistent activation of immune and non-immune cells, thus leading to a condition of arterial chronic inflammation with plaque formation and rupture in complicated cases. In particular, the effects of bacteria, viruses and their toxic products as well as of glycated lipoproteins will be illustrated with special reference to the main inflammatory pathways triggered by a persistent antigenic load in the host. Taking into consideration this broad variety of antigens implicated in the pathogenesis of atherosclerosis, therapeutic approaches such as antibiotics, dietary intervention and immune therapies will be discussed.

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The Oxazolidinone Derivative Locostatin Induces Cytokine Appeasement

Cited by 17 publications

References 45 publications

RKIP Contributes to IFN-γ Synthesis by CD8+ T Cells after Serial TCR Triggering in Systemic Inflammatory Response Syndrome

RKIP Contributes to IFN-γ Synthesis by CD8+ T Cells after Serial TCR Triggering in Systemic Inflammatory Response Syndrome

Responses to LPS boost effector CD8 T-cell accumulation outside of signals 1 and 2

A Broad Variety of Antigens Contribute to the Pathogenesis of Atherosclerosis: How to Neutralize Noxious Reactions in the Host

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