Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

Harling, Kirstin; Adankwah, Ernest; Güler, Alptekin; Awuah, Anthony Afum-Adjei; Adu-Amoah, Louis; Mayatepek, Ertan; Owusu‐Dabo, Ellis; Nausch, Norman; Jacobsen, Marc

doi:10.1038/cmi.2018.5

Cited by 60 publications

(69 citation statements)

References 59 publications

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“…Hydrostatin-SN10 treatment significantly reduced the number of apoptotic cells via the inhibition of the IL-6 and protein levels of proapoptotic biomarkers, such as caspase 3 and BAX, and increase of antiapoptotic biomarkers Bcl2 (Figures 4, 6, and 8). Previous studies have shown that IL-6 restores the phosphorylation of STAT3 [28], thereby promoting the apoptosis of lung cells, and our present findings was consistent with the reports.…”

Section: Discussionsupporting

confidence: 93%

Hydrostatin-SN10 Ameliorates Pancreatitis-Induced Lung Injury by Affecting IL-6-Induced JAK2/STAT3-Associated Inflammation and Oxidative Stress

Piao¹,

Zou

Sui

et al. 2019

Oxidative Medicine and Cellular Longevity

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Hydrostatin-SN1 (peptide sequence, DEQHLETELHTLTSVLTANGFQ), a kind of peptides extracted from snake venom, has been reported to have anti-inflammatory effect, but its truncated mutant hydrostatin-SN10 (peptide sequence, DEQHLETELH) on pancreatitis-induced acute lung injury has not been well documented. Interleukin- (IL-) 6-induced Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway is involved with inflammatory and oxidative stress activities and may be associated with the pathogenesis of lung injury, and related molecules were measured. Taurocholate-induced pancreatitis associated with acute lung injury was established and treated with hydrostatin-SN10. Pancreatitis was confirmed by measuring the serum levels of amylase, lipase, and trypsinogen and urinary amylase. Lung injury was determined by histologically assessing acinar cell changes. The related molecules of IL-6-induced JAK2/STAT3-associated inflammation and oxidative stress were quantitated by real time-PCR, Western blot, and/or immunochemical assay. Hydrostatin-SN10 reduced the levels of serum amylase, lipase, and trypsinogen and urinary amylase when compared with the model group (p < 0.05). Hydrostatin-SN10 significantly inhibited the IL-6-stimulated JAK2/STAT3 pathway and reduced the number of apoptotic cells via the downregulation of caspase 3 and BAX (proapoptotic) and upregulation of Bcl2 (antiapoptotic) (p < 0.05). IL-6 induced the increase in the levels of JAK2 and STAT3, which was reversed by hydrostatin-SN10 treatment (p < 0.05). In addition, hydrostatin-SN10 reduced the expression of IL-6 and TNF- (tumor necrosis factor-) α and increased the level of IL-10 (p < 0.05). On the other hand, hydrostatin-SN10 treatment increased the levels of superoxide dismutase (SOD) and reduced glutathione (GSH) and the levels of malondialdehyde (MDA) and alanine aminotransferase (ALT) (p < 0.05). These results suggest that hydrostatin-SN10 may inhibit pancreatitis-induced acute lung injury by affecting IL-6-mediated JAK2/STAT3 pathway-associated inflammation and oxidative stress.

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Section: Discussionsupporting

confidence: 93%

Hydrostatin-SN10 Ameliorates Pancreatitis-Induced Lung Injury by Affecting IL-6-Induced JAK2/STAT3-Associated Inflammation and Oxidative Stress

Piao¹,

Zou

Sui

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…We next examined the molecular mechanisms by which IL6 promotes glioma cancer stemness. Previous studies have clearly shown that IL6 exerts its effects through the JAK1-STAT3 signal transduction pathway [30][31][32]. Similarly, we observed that the phosphorylation of STAT3 (p-STAT3) was activated in the IL6 recombinant protein treatment in glioma cells ( Figure 5F).…”

Section: Il6 Promotes Glioma Cancer Stemness Via Stat3 Activationsupporting

confidence: 80%

Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

Zhang

Wang

et al. 2020

Preprint

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Background: Glioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and the tumor microenvironment (TME). The aim of this study was to examine how regulatory T cells (Tregs) increase the stemness and tumorigenic potential of glioma cells.Methods: Tumor and peripheral blood samples were collected during surgery from 86 patients with glioma, and 75 samples of adjacent noncancerous tissue were collected, and Regulatory T cells (Tregs) were extracted from blood. Cytological and histochemical analyses were conducted to examine the mechanisms of Treg action on cancer cells. A mouse glioma model was used.Results: Intense infiltration by Tregs facilitated the qualities of GSCs through TGF-β secretion, which helped to coordinate tumor growth. Mechanistic investigations indicated that TGF-b acted on cancer cells to induce expression of the core cancer stem cell-related genes ( CD133, SOX2, NESTIN, MUSASHI1, and ALDH1A ) and to induce sphere formation via the NF-κB–IL6–STAT3 signaling pathway, resulting in increased cancer stemness and tumorigenic potential. Tregs promoted glioma tumor growth, and this effect was abrogated by blockade of the IL6 receptor by tocilizumab, which also demonstrated some therapeutic efficacy in a xenograft model. Expression levels of CD133, IL6 and TGF-β were found to serve as prognostic markers for glioma.Conclusions: Our findings reveal a new immune-associated mechanism underlying Treg-induced GSCs. Efforts to target this network may provide an effective strategy for treating glioma.

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“…However, intracellular IFN-γ measurements in purified PBMCs largely reversed impaired T-cell response to PHA in tuberculosis patients, indicating that serum factors at least partially accounted for impaired PHA induced T-cell response. A possible explanation would be high levels of inflammatory and regulatory cytokines found in serum of patients with acute tuberculosis (26, 27). Recently, we showed that high serum IL-10 and IL-6 levels were accompanied by constitutive STAT3 phosphorylation and SOCS3 expression (27).…”

Section: Discussionmentioning

confidence: 99%

“…A possible explanation would be high levels of inflammatory and regulatory cytokines found in serum of patients with acute tuberculosis (26, 27). Recently, we showed that high serum IL-10 and IL-6 levels were accompanied by constitutive STAT3 phosphorylation and SOCS3 expression (27). Especially SOCS3 correlated negatively with T-cell IFN-γ production and may therefore contribute to low PHA response (27).…”

Section: Discussionmentioning

confidence: 99%

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Two-Hit in vitro T-Cell Stimulation Detects Mycobacterium tuberculosis Infection in QuantiFERON Negative Tuberculosis Patients and Healthy Contacts From Ghana

et al. 2019

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IFN-γ release assays [e.g., QuantiFERON (QFT)] are widely used for diagnosis of Mycobacterium tuberculosis ( Mtb ) infection. T-cell responses against QFT antigens ESAT6 and CFP10 are highly Mtb specific but previous studies indicated suboptimal assay sensitivity. Especially for potentially infected healthy contacts (HCs) of tuberculosis patients, alternative antigen usage and more sensitive tests may contribute to improved detection of latent Mtb infection. In a pilot case-control study of tuberculosis patients ( n = 22) and HCs ( n = 20) from Ghana, we performed multifaceted in vitro assays to identify optimal assay conditions. This included a two-hit stimulation assay, which is based on initial and second re-stimulation with the same antigen on d6 and intracellular IFN-γ analysis, to compare T-cell responses against ESAT6/CFP10 (E6/C10) and selected latency antigens (i.e. Rv2628, Rv1733, Rv2031, Rv3407) of Mtb . Considerable subgroups of tuberculosis patients (64%) and HCs (75%) had negative or indeterminate QFT results partially accompanied by moderate PHA induced responses and high IFN-γ background values. Intracellular IFN-γ analysis of E6/C10 specific CD4 + T-cell subpopulations and evaluation of responder frequencies had only moderate effects on assay sensitivity. However, two-hit in vitro stimulation significantly enhanced E6/C10 specific IFN-γ positive T-cell proportions especially in QFT non-responders, and in both study groups. Mtb latency antigen-specific T cells against Rv1733 and Rv2628 were especially detected in HCs after two-hit stimulation and T-cell responses against Rv2628 were highly capable to discriminate tuberculosis patients and HCs. Two-hit in vitro stimulation may improve moderate sensitivity of short term IFN-γ based assays, like QFT, to detect Mtb infection. Latency stage-specific antigens added significantly to detection of Mtb infection in HCs and tuberculosis patients with negative QFT test results.

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Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

Cited by 60 publications

References 59 publications

Hydrostatin-SN10 Ameliorates Pancreatitis-Induced Lung Injury by Affecting IL-6-Induced JAK2/STAT3-Associated Inflammation and Oxidative Stress

Hydrostatin-SN10 Ameliorates Pancreatitis-Induced Lung Injury by Affecting IL-6-Induced JAK2/STAT3-Associated Inflammation and Oxidative Stress

Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

Two-Hit in vitro T-Cell Stimulation Detects Mycobacterium tuberculosis Infection in QuantiFERON Negative Tuberculosis Patients and Healthy Contacts From Ghana

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