scholarly journals TNF deficiency dysregulates inflammatory cytokine production leading to lung pathology and death during respiratory poxvirus infection

2019 ◽  
Author(s):  
Ma. Junaliah Tuazon Kels ◽  
Esther Ng ◽  
Zahrah Al Rumaih ◽  
Pratikshya Pandey ◽  
Sigrid R. Ruuls ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Cytokine Signaling ◽  
Lung Pathology ◽  
Suppressor Of Cytokine Signaling ◽  
Inflammatory Cytokine Production ◽  
Significant Pathology ◽  
Ifn Γ ◽  
Necrosis Factor ◽  
Severe Lung

AbstractExcessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF-/-) also caused significant pathology during respiratory ectromelia virus (ECTV) infection, a surrogate mouse model for smallpox. TNF-/- mice succumbed to fulminant disease whereas wild-type mice, and those expressing only transmembrane TNF, recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines IL-6, IL-10, TGF-β, and IFN-γ. Blockade of these cytokines reduced lung pathology concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Short-term inhibition of STAT3 activation in ECTV-infected TNF-/- mice with an inhibitor reduced lung pathology. TNF is essential for regulating inflammation and its deficiency exacerbates ECTV infection as a consequence of significant lung pathology caused by dysregulation of inflammatory cytokine production, in part via overactivation of STAT3.

scholarly journals Poxvirus-encoded TNF receptor homolog dampens inflammation and protects from uncontrolled lung pathology during respiratory infection

2020 ◽  
Vol 117 (43) ◽  
pp. 26885-26894
Author(s):  
Zahrah Al Rumaih ◽  
Ma. Junaliah Tuazon Kels ◽  
Esther Ng ◽  
Pratikshya Pandey ◽  
Sergio M. Pontejo ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Tumor Necrosis Factor Receptor ◽  
Binding Domain ◽  
Lung Pathology ◽  
Protective Effects ◽  
Inflammatory Cytokine Production ◽  
Reverse Signaling ◽  
Ifn Γ

Ectromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both orthopoxviruses encode tumor necrosis factor receptor (TNFR) homologs or viral TNFR (vTNFR). These homologs are termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain called smallpox virus-encoded chemokine receptor (SECRET) domain. ECTV encodes one vTNFR known as CrmD. Infection of ECTV-resistant C57BL/6 mice with a CrmD deletion mutant virus resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production. CrmD dampened pathology, leukocyte recruitment, and inflammatory cytokine production in lungs including TNF, IL-6, IL-10, and IFN-γ. Blockade of TNF, IL-6, or IL-10R function with monoclonal antibodies reduced lung pathology and provided 60 to 100% protection from otherwise lethal infection. IFN-γ caused lung pathology only when both the TNF-binding and SECRET domains were absent. Presence of the SECRET domain alone induced significantly higher levels of IL-1β, IL-6, and IL-10, likely overcoming any protective effects that might have been afforded by anti–IFN-γ treatment. The use of TNF-deficient mice and those that express only membrane-associated but not secreted TNF revealed that CrmD is critically dependent on host TNF for its function. In vitro, recombinant Crm proteins from different orthopoxviruses bound to membrane-associated TNF and dampened inflammatory gene expression through reverse signaling. CrmD does not affect virus replication; however, it provides the host advantage by enabling survival. Host survival would facilitate virus spread, which would also provide an advantage to the virus.

scholarly journals Poxvirus-encoded TNF receptor homolog dampens inflammation and protects the host from uncontrolled lung pathology and death during respiratory infection

2020 ◽  
Author(s):  
Zahrah Al Rumaih ◽  
Ma. Junaliah Tuazon Kels ◽  
Esther Ng ◽  
Pratikshya Pandey ◽  
Sergio M. Pontejo ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Tumor Necrosis Factor Receptor ◽  
Binding Domain ◽  
Lung Pathology ◽  
Tnf Receptor ◽  
Response Modifier ◽  
Inflammatory Cytokine Production ◽  
Lethal Infection ◽  
Ifn Γ ◽  
Necrosis Factor

AbstractEctromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both viruses encode tumor necrosis factor receptor (TNFR) homologs termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain termed smallpox virus-encoded chemokine receptor (SECRET) domain. Infection of ECTV-resistant C57BL/6 mice with an ECTV CrmD deletion mutant resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production but viral load was not affected. CrmD dampened lung pathology, leukocyte recruitment and inflammatory cytokines including TNF, IL-6, IL-10 and IFN-γ. Blockade of IL-6, IL-10R or TNF function with monoclonal antibodies reduced lung pathology and provided 60-100% protection from an otherwise lethal infection. IFN-γ caused lung pathology only when both the TNF-binding and SECRET domains were deleted but it was neither necessary nor sufficient to cause pathology when only the CrmD SECRET domain was expressed by virus.

scholarly journals Fosfomycin Alters Lipopolysaccharide-Induced Inflammatory Cytokine Production in Mice

1999 ◽  
Vol 43 (3) ◽  
pp. 697-698 ◽  
Author(s):  
Tetsuya Matsumoto ◽  
Kazuhiro Tateda ◽  
Shuichi Miyazaki ◽  
Nobuhiko Furuya ◽  
Akira Ohno ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Serum Levels ◽  
Necrosis Factor Alpha ◽  
Inflammatory Cytokine Production ◽  
Factor Alpha ◽  
Lps Treatment ◽  
Necrosis Factor

ABSTRACT To determine the mechanisms of immunomodulating action of fosfomycin (FOF), we examined its effect on the production of inflammatory cytokines in mice injected with lipopolysaccharide (LPS). Treatment with FOF significantly lowered the peak serum levels of tumor necrosis factor alpha and interleukin-1β, indicating that FOF alters inflammatory cytokine production after LPS stimulation.

scholarly journals Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4322
Author(s):  
Sergio Ramírez-Pérez ◽  
Luis Alexis Hernández-Palma ◽  
Edith Oregon-Romero ◽  
Brian Uriel Anaya-Macías ◽  
Samuel García-Arellano ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Primary Response ◽  
Peripheral Blood Mononuclear ◽  
Inflammatory Cytokine Production ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Pathway Inhibition

The inflammatory process implicates homeostasis disruption and increased production of inflammatory mediators. Myeloid differentiation primary response 88 (MyD88) is an essential protein recruited after lipopolysaccharide (LPS) and interleukin (IL)-1β stimulation, a process that converges in nuclear factor kappa B (NF-κB) activation, as well as a transcription of several genes of both pro- and anti-inflammatory cytokines. The inhibition of MyD88 has shown efficacy by decrease inflammatory response, and has demonstrated potential application as a therapeutic target in chronic diseases. In this study, we investigate the effect of MyD88 dimerisation inhibitor ST2825 on cytokine production from rhIL-1β and LPS-stimulated peripheral blood mononuclear cells (PBMC) from healthy blood donors (HBD). ST2825 significantly downregulates the production of IFN-γ, IL-6, IL-12, IL-2, IL-15, IL-7, VEGF, IL-1Ra, IL-4, IL-5, IL-13 and IL-9 (p < 0.05) in LPS-stimulated PBMC. Moreover, ST2825 had a relatively low impact on IL-1β signalling pathway inhibition, showing that only a few specific cytokines, such as IFN-γ and IL-1Ra, are inhibited in rhIL-1β-stimulated PBMC (p < 0.01). In conclusion, MyD88 dimerisation inhibitor ST2825 showed high efficacy by inhibiting pro- and anti-inflammatory cytokine production in LPS-stimulated PBMC. Moreover, although rhIL-1β induced a sustained cytokine production (p < 0.05), ST2825 did not show a significant effect in the secretion of neither pro- nor anti-inflammatory cytokines in rhIL-1β-stimulated PBMC.

scholarly journals Pathogen recognition by NK cells amplifies the pro-inflammatory cytokine production of monocyte-derived DC via IFN-γ

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Tammy Oth ◽  
Thomas H. P. M. Habets ◽  
Wilfred T. V. Germeraad ◽  
Marijke I. Zonneveld ◽  
Gerard M. J. Bos ◽  
...  
Keyword(s):  
Nk Cells ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Pathogen Recognition ◽  
Inflammatory Cytokine Production ◽  
Ifn Γ

scholarly journals Gentian Violet modulates cytokines levels in mice spleen toward an anti-inflammatory profile

2020 ◽  
Author(s):  
Salam Jbeili ◽  
Mohamad Rima ◽  
Abdul Rahman Annous ◽  
Abdo Ibrahim Berro ◽  
Ziad Fajloun ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Gentian Violet ◽  
Immunomodulatory Effects ◽  
Inflammatory Cytokine Production ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Inflammatory Profile ◽  
Exact Effect

Abstract Introduction: Gentian Violet (GV) is a triphenylmethane industrial dye that is known for its antibacterial, antiviral, anti-helminthic and anti-tumor effects. Although many studies focused on determining the biological and pharmacological applications of GV, its exact effect on the immune response has not been elucidated yet.Methods: In this study, we investigate the immunomodulatory effects of GV in BALB/c mice after intraperitoneal injection of the dye by assessing cytokines levels in the spleen.Results: Our data show that GV-treated mice have decreased level of proinflammatory cytokines (IL-1β and TNF-α) and increased level of anti-inflammatory cytokines (IL-4) in their spleens. In addition, IFN-γ that can modulate pro-inflammatory cytokine production was upregulated in GV-treated mice. Conclusion: Together, these findings suggest an anti-inflammatory activity of GV that warrant further studies investigating the potential of GV in immunotherapy.

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