Tu1123 Acid and Bile Salts Activate Hypoxia Inducible Factor (HIF)-2α and Increase Transcription of HIF-Target PRO-Inflammatory Cytokines in Esophageal Squamous Cell Lines: A Potential Mechanism for the Pathogenesis of Reflux Esophagitis

2012 ◽  
Vol 142 (5) ◽  
pp. S-752-S-753
Author(s):  
Xiaofang Huo ◽  
Qiuyang Zhang ◽  
Chunhua Yu ◽  
Xi Zhang ◽  
Edaire Cheng ◽  
...  
Keyword(s):  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Squamous Cell ◽  
Reflux Esophagitis ◽  
Bile Salts ◽  
Hypoxia Inducible Factor ◽  
Potential Mechanism ◽  
Pro Inflammatory Cytokines

scholarly journals Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury

2019 ◽  
Vol 20 (7) ◽  
pp. 1678 ◽  
Author(s):  
Yi-Chen Lee ◽  
Chun-Yu Lin ◽  
Yen-Hsu Chen ◽  
Wen-Chin Chiu ◽  
Yen-Yun Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Bronchial Epithelial Cell ◽  
Bronchial Epithelial ◽  
Epithelial Cell Lines ◽  
Nfκb Pathway ◽  
Pro Inflammatory Cytokines

Acute lung injury (ALI) is a life-threatening syndrome characterized by acute and severe hypoxemic respiratory failure. Visfatin, which is known as an obesity-related cytokine with pro-inflammatory activities, plays a role in regulation of inflammatory cytokines. The mechanisms of ALI remain unclear in critically ill patients. Survival in ALI patients appear to be influenced by the stress generated by mechanical ventilation and by ALI-associated factors that initiate the inflammatory response. The objective for this study was to understand the mechanisms of how visfatin regulates inflammatory cytokines and promotes ALI. The expression of visfatin was evaluated in ALI patients and mouse sepsis models. Moreover, the underlying mechanisms were investigated using human bronchial epithelial cell lines, BEAS-2B and NL-20. An increase of serum visfatin was discovered in ALI patients compared to normal controls. Results from hematoxylin and eosin (H&E) and immunohistochemistry staining also showed that visfatin protein was upregulated in mouse sepsis models. Moreover, lipopolysaccharide (LPS) induced visfatin expression, activated the STAT3/NFκB pathway, and increased the expression of pro-inflammatory cytokines, including IL1-β, IL-6, and TNF-α in human bronchial epithelial cell lines NL-20 and BEAS-2B. Co-treatment of visfatin inhibitor FK866 reversed the activation of the STAT3/NFκB pathway and the increase of pro-inflammatory cytokines induced by LPS. Our study provides new evidence for the involvement of visfatin and down-stream events in acute lung injury. Further studies are required to confirm whether the anti-visfatin approaches can improve ALI patient survival by alleviating the pro-inflammatory process.

(+)-Altholactone exhibits broad spectrum immune modulating activity by inhibiting the activation of pro-inflammatory cytokines in RAW 264.7 cell lines

2013 ◽  
Vol 21 (14) ◽  
pp. 4358-4364 ◽  
Author(s):  
Tyler A. Johnson ◽  
Johann Sohn ◽  
Aidan E. Ward ◽  
Tanya L. Cohen ◽  
Nicholas D. Lorig-Roach ◽  
...  
Keyword(s):  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Broad Spectrum ◽  
Raw 264.7 ◽  
Raw 264.7 Cell ◽  
Pro Inflammatory Cytokines

scholarly journals Effects of IL-1β, IL-20, and BMP-2 on Intervertebral Disc Inflammation under Hypoxia

2020 ◽  
Vol 9 (1) ◽  
pp. 140 ◽  
Author(s):  
Yu-Hsiang Hsu ◽  
Ruey-Mo Lin ◽  
Yi-Shu Chiu ◽  
Wen-Lung Liu ◽  
Kuo-Yuan Huang
Keyword(s):  
Intervertebral Disc ◽  
Inflammatory Cytokines ◽  
Disc Herniation ◽  
Healing Process ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Bone Morphogenetic Protein 2 ◽  
Intervertebral Disc Herniation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Pro Inflammatory Cytokines

Intervertebral disc (IVD) is an avascular tissue under hypoxic condition after adulthood. Our previous data showed that inflammatory cytokines (interleukin (IL)-1β), IL-20, and bone morphogenetic protein-2 (BMP-2) play important roles in the healing process after disc injury. In the current study, we investigated whether IL-1β, IL-20, or BMP-2 modulate the expression of pro-inflammatory cytokines, chemotaxis factor, and angiogenesis factor on IVD cells under hypoxia. IVD cells were isolated from patients with intervertebral disc herniation (HIVD) at the levels of L4–5 and L5–S1. We found that the expression of IL-1β, IL-20, BMP-2, hypoxia-inducible factor (HIF)-1α, IL-6, IL-8, angiogenetic factor (vascular endothelial growth factor (VEGF)), chemotactic factor (monocyte chemoattractant protein 1 (MCP-1)), and matrix metalloproteinase-3 (MMP-3) was upregulated in IVD cells under hypoxia conditions. In addition, IL-1β upregulated the expression of pro-inflammatory cytokines (IL-6 and IL-8), VEGF, MCP-1, and disc degradation factor (MMP-3) in IVD cells under hypoxia conditions. IL-20 upregulated MCP-1 and VEGF expression. BMP-2 also upregulated the expression of MCP-1, VEGF, and IL-8 in IVD cells under hypoxia conditions. Treatment with antibody against IL-1β decreased VEGF and MMP-3 expression, while treatment with IL-20 or BMP-2 antibodies decreased MCP-1, VEGF, and MMP-3 expression. Moreover, IL-1β modulated both the expression of IL-20 and BMP-2, but IL-20 only modulated BMP-2 either under a hypoxic or normoxic condition. Therefore, we concluded that the inflammation, chemotaxis, matrix degradation, and angiogenesis after disc herniation are influenced by the hypoxic condition and controlled by IL-1β, IL-20, and BMP-2.

Constitutive Expression of CD40L by CAR-Modified Tumor Targeted T Cells Enhances Anti-Tumor Efficacy Both in Vitro and in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4120-4120 ◽  
Author(s):  
Kevin J. Curran ◽  
Beatrijs Seinstra ◽  
Yan Nikhamin ◽  
Raymond Yeh ◽  
Yelena Usachenko ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Adhesion Molecules ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Cd40 Ligand ◽  
Tumor Cell Lines ◽  
Pro Inflammatory Cytokines

Abstract Abstract 4120 T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). Recent reports have demonstrated the effectiveness of CAR modified T cells in patients with relapsed or refractory malignancies. However, CAR modified T cells have yet to demonstrate the ability to recruit an endogenous anti-tumor response which would greatly enhance their therapeutic benefit. To overcome these limitations we have developed a bi-cistronic gamma-retroviral vector allowing for constitutive co-expression of a CD19-specific CAR (19–28z) and human CD40 ligand (CD40L; CD154). The CD40 ligand/CD40 system has been demonstrated to activate dendritic cells (DCs) and alter the phenotype of B cells (upregulation of co-stimulatory and adhesion molecules and secretion of pro-inflammatory cytokines) with subsequent stimulation of CD8+ T cell activation and proliferation. We now demonstrate T cells genetically modified to constitutively express CD40L undergo enhanced proliferation and up-regulated secretion of pro-inflammatory cytokines including GM-CSF and INF-g. Furthermore, T cells modified to constitutively express CD40L, upon co-culture, will alter the phenotype of CD40+ B cell tumor cell lines by enhancing the expression co-stimulatory molecules (CD80/CD86), adhesion molecules (CD54/CD58/CD70) and death receptors (CD95; Fas). These findings were similarly evident in primary patient tumor samples (e.g. CLL cells) when co-cultured with autologous T cells modified to constitutively express CD40L. We further demonstrate maturation of monocyte derived DCs with subsequent secretion of IL-12 following co-culture with autologous T cells modified to constitutively express CD40L. T cells transduced with the bi-cistronic 19–28z/CD40L vector showed enhanced in vitro cytotoxicity against a panel of CD19+ tumor cell lines. Furthermore, infusion of 19–28z/CD40L modified T cells enhances the survival of CD19+ tumor bearing immunodeficient mice (SCID/Beige) when compared to mice treated with T cells modified to express the anti-CD19 19–28z CAR alone. We conclude that further genetic modification of CAR targeted T cells to constitutively express the co-stimulatory CD40L may enhance the anti-tumor efficacy of this adoptive T cell therapy. Our data suggests this enhanced T cell efficacy may be due to both autocrine and paracrine mediated mechanisms. Disclosures: No relevant conflicts of interest to declare.

eFT508, a Potent and Selective Mitogen-Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 Inhibitor, Is Efficacious in Preclinical Models of Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1554-1554 ◽  
Author(s):  
Kevin R. Webster ◽  
Vikas K Goel ◽  
Ivy NJ Hung ◽  
Gregory S Parker ◽  
Jocelyn Staunton ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Mechanism Of Action ◽  
B Cell Lymphoma ◽  
Human Lymphoma ◽  
Equity Ownership ◽  
The Stability ◽  
Dose Dependent ◽  
Pro Inflammatory Cytokines

Abstract Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors and hematological malignancies. MNK1 and MNK2 integrate signals from several oncogenic and immune signaling pathways, including RAS, p38, and Toll-like receptor (TLR) pathways, by phosphorylating eukaryotic initiation factor 4E (eIF4E) and other key effector proteins including hnRNPA1 and PSF. Through phosphorylation of these regulatory proteins MNK1 and MNK2 selectively regulate the stability and translation of a subset of cellular mRNA. eFT508 is a potent, highly selective, and orally bioavailable MNK1 and MNK2 inhibitor. eFT508 has a half-maximal inhibitory concentration (IC50) of 1-2 nM against both MNK isoforms in enzyme assays and inhibits the kinase through a reversible, ATP-competitive mechanism of action. Treatment of tumor cell lines with eFT508 led to a dose-dependent reduction in eIF4E phosphorylation at serine 209 (IC50 = 2-16 nM), consistent with previous findings that phosphorylation of this site is solely dependent upon MNK1/MNK2. In a panel of ~50 hematological cancers, eFT508 showed anti-proliferative activity against multiple DLBCL cell lines. Sensitivity to eFT508 in TMD8, OCI-Ly3 and HBL1 DLBCL cell lines was associated with dose-dependent decreases in production of pro-inflammatory cytokines including TNFα, IL-6, IL-10 and CXCL10. Further evaluation eFT508 mechanism of action demonstrated that decreased TNFα production correlated with a 2-fold decrease in TNFα mRNA half-life. These findings are consistent with MNK1 phosphorylation of specific RNA-binding proteins, eg, hnRNPA1, that regulate the stability and translation of mRNA containing specific AU-rich elements (ARE) in their 3'-untranslated regions (UTR). Pro-inflammatory cytokines are drivers of key hallmarks of cancer including tumor cell survival, migration and invasion, angiogenesis, and immune evasion, while also driving drug resistance. Therefore, eFT508 was tested in vivo in 7 subcutaneous human lymphoma xenograft models. Significant anti-tumor activity was observed in the TMD8 and HBL-1 ABC-DLBCL models, both of which harbor activating MyD88 mutations. In addition, eFT508 combined effectively with components of R-CHOP and with novel targeted agents, including ibrutinib and venetoclax, in human lymphoma models. These results underscore the potential of eFT508 for the treatment of DLBCL. eFT508 has also been characterized in nonclinical safety pharmacology and toxicology studies. Clinical trials in patients with hematological and other malignancies are planned. Disclosures Webster: Effector Therapeutics: Employment. Goel:Effector Therapeutics: Employment. Hung:Effector Therapeutics: Employment. Parker:Effector Therapeutics: Employment. Staunton:Effector Therapeutics: Employment. Neal:Effector Therapeutics: Employment. Molter:Effector Therapeutics: Employment. Chiang:Effector Therapeutics: Employment. Jessen:Effector Therapeutics: Equity Ownership. Wegerski:Effector Therapeutics: Employment. Sperry:Effector Therapeutics: Employment. Huang:Effector Therapeutics: Employment. Chen:Effector Therapeutics: Employment. Thompson:Effector Therapeutics: Employment. Appleman:Effector Therapeutics: Employment. Webber:Effector Therapeutics: Equity Ownership. Sprengeler:Effector Therapeutics: Employment. Reich:Effector Therapeutics: Employment.

Melatonin attenuates methamphetamine-induced overexpression of pro-inflammatory cytokines in microglial cell lines

2010 ◽  
Vol 48 (4) ◽  
pp. 347-352 ◽  
Author(s):  
Jiraporn Tocharus ◽  
Chakkrapong Khonthun ◽  
Sukumal Chongthammakun ◽  
Piyarat Govitrapong
Keyword(s):  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Microglial Cell ◽  
Pro Inflammatory Cytokines

scholarly journals Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2340
Author(s):  
Mykyta I. Malkov ◽  
Chee Teik Lee ◽  
Cormac T. Taylor
Keyword(s):  
Inflammatory Cytokines ◽  
Cellular Response ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Wide Range ◽  
Inflammatory Stimuli ◽  
Factor Α ◽  
Hif Pathway ◽  
The Impact ◽  
Pro Inflammatory Cytokines

Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.

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