Therapeutics targeting innate immune/inflammatory responses through the interleukin-6/JAK/STAT signal transduction pathway in patients with cancer

Roxburgh, Campbell S.D.; McMillan, Donald C.

doi:10.1016/j.trsl.2015.08.013

Cited by 41 publications

(27 citation statements)

References 60 publications

(53 reference statements)

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“…The pleiotropic JAK/STAT pathway signals a cascade of reactions to maintain homeostasis [125]. The liability score for SNPs in IL4R predicted changes in the trajectory of morning fatigue.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy

et al. 2017

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Fatigue, a highly prevalent and distressing symptom during chemotherapy (CTX), demonstrates diurnal and interindividual variability in severity. Little is known about the associations between variations in genes involved in inflammatory processes and morning and evening fatigue severity during CTX. The purposes of this study, in a sample of oncology patients (N=543) with breast, gastrointestinal (GI), gynecological (GYN), or lung cancer who received two cycles of CTX, were to determine whether variations in genes involved in inflammatory processes were associated with inter-individual variability in initial levels as well as in the trajectories of morning and evening fatigue. Patients completed the Lee Fatigue Scale to determine morning and evening fatigue severity a total of six times over two cycles of CTX. Using a whole exome array, 309 single nucleotide polymorphisms among the 64 candidate genes that passed all quality control filters were evaluated using hierarchical linear modeling (HLM). Based on the results of the HLM analyses, the final SNPs were evaluated for their potential impact on protein function using two bioinformational tools. The following inflammatory pathways were represented: chemokines (3 genes); cytokines (12 genes); inflammasome (11 genes); Janus kinase/signal transducers and activators of transcription (JAK/STAT, 10 genes); mitogen-activated protein kinase/jun amino-terminal kinases (MAPK/JNK, 3 genes); nuclear factor-kappa beta (NFkB, 18 genes); and NFkB and MAP/JNK (7 genes). After controlling for self-reported and genomic estimates of race and ethnicity, polymorphisms in six genes from the cytokine (2 genes); inflammasome (2 genes); and NFkB (2 genes) pathways were associated with both morning and evening fatigue. Polymorphisms in six genes from the inflammasome (1 gene); JAK/STAT (1 gene); and NFkB (4 genes) pathways were associated with only morning fatigue. Polymorphisms in three genes from the inflammasome (2 genes) and the NFkB (1 gene) pathways were associated with only evening fatigue. Taken together, these findings add to the growing body of evidence that suggests that morning and evening fatigue are distinct symptoms.

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“…The pleiotropic JAK/STAT pathway signals a cascade of reactions to maintain homeostasis [125]. The liability score for SNPs in IL4R predicted changes in the trajectory of morning fatigue.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy

et al. 2017

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“…IL-6 is able to worsen myocardial hypertrophy via activating the JAK/STAT pathway (21). The JAK/STAT pathway mediates the reduction in synthesis of the surface-active materials of pulmonary epithelial cells caused by oxidative stress (22).…”

Section: Discussionmentioning

confidence: 99%

The effect of hydroxy safflower yellow A on coronary heart disease through Bcl‑2/Bax and PPAR‑γ

Zhou

Wang

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to investigate the effect of hydroxy safflower yellow A (HSYA) on coronary heart disease through assessing the expression of B-cell lymphoma 2 (Bcl-2)/Bcl-2-like protein 4 (Bax) and peroxisome proliferator-activated receptor (PPAR)-γ. Coronary heart disease was induced in male Bama miniature swines via thoracoscope to serve as an animal model. Coronary heart disease swine were lavaged with 20 or 40 mg/kg HSYA. The mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-10, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected using reverse transcription-quantitative polymerase chain reaction. The protein expression of Bcl-2, Bax, PPAR-γ, phosphorylation of Janus kinase (JAK)2 and phosphorylation of signal transducer and activator of transcription (STAT)3 were detected using western blot analysis. Treatment with HSYA significantly suppressed the mRNA levels of IL-1β (P<0.01), IL-6 (P<0.01), TNF-α (P<0.01), COX-2 (P<0.01) and iNOS (P<0.01), and significantly increased IL-10 mRNA level in the coronary heart disease model (P<0.01). Furthermore, HSYA treatment significantly decreased the Bcl-2/Bax ratio (P<0.01) in the coronary heart disease model group, and enhanced the phosphorylation of JAK2/STAT3 pathway (P<0.01). However, HSYA had no significant effect on the expression of PPAR-γ protein. The results of the present study suggest that HSYA is able to weaken coronary heart disease via inflammation, Bcl-2/Bax and the PPAR-γ signaling pathway.

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“…To explore the in-depth mechanism of TF expression, the protein levels of TF, NF-κB p65, and c-JUN were measured by western blot analysis. 45 Activated IL-6 receptor signal transduction components, glycoprotein 130, lead to the phosphorylation of the downstream protein JAK and phosphorylate their associated receptors to provide multiple binding sites for the signaling proteins. 5).…”

Section: Papermentioning

confidence: 99%

Fine particulate matter induces vascular endothelial activation via IL-6 dependent JAK1/STAT3 signaling pathway

et al. 2016

Toxicol. Res.

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Exposure to PM2.5 has been strongly linked to endothelial dysfunction. However, the underlying mechanism of PM2.5 on the vascular endothelial function is poorly understood. This study examined the toxic effect and underlying mechanism of PM2.5 on human umbilical vein endothelial cells (HUVECs). Decreased cell viability and increased LDH activity were observed in the PM2.5-treated HUVECs in a dose-dependent manner. The production of ROS, MDA, and the inhibition of SOD activity were also triggered by PM2.5 in HUVECs. In addition, PM2.5 increased the intracellular levels of proinflammatory cytokines (IL-6, TNF-a, IL-1β, IL-8 and CRP), cell adhesion molecules (ICAM-1, VCAM-1) and tissue factor (TF), resulted in endothelial activation. For an in-depth study, the protein levels of IL-6, JAK1 and STAT3 were up-regulated significantly, while the expression of JAK2 and SOCS1 were down-regulated gradually in PM2.5-treated HUVECs in a dose-dependent manner. These results show that PM2.5 triggered endothelial activation upregulation of the IL-6 dependent JAK1/STAT3 signaling pathway. This will provide new insights into the toxic effects and mechanisms of cardiovascular diseases triggered by ambient air pollution.

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Therapeutics targeting innate immune/inflammatory responses through the interleukin-6/JAK/STAT signal transduction pathway in patients with cancer

Cited by 41 publications

References 60 publications

Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy

Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy

The effect of hydroxy safflower yellow A on coronary heart disease through Bcl‑2/Bax and PPAR‑γ

Fine particulate matter induces vascular endothelial activation via IL-6 dependent JAK1/STAT3 signaling pathway

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