Activin A regulates activation of mouse neutrophils by Smad3 signalling

Qi, Yan; Ge, Jingyan; Ma, Chunhui; Wu, Na; Cui, Xueling; Liu, Zhonghui

doi:10.1098/rsob.160342

Cited by 22 publications

(13 citation statements)

References 44 publications

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“…The involvement of activin A in IL‐6 secretion has also been described in non‐cancerous cells, like mouse neutrophils, where the cells in response to LPS secrete IL‐6 in an activin A/SMAD3‐dependent manner . IL‐6 may act systemically and has been suggested to be one of the major contributors to cachexia .…”

Section: Discussionmentioning

confidence: 94%

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Pettersen

Andersen

Veen

et al. 2019

J cachexia sarcopenia muscle

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Background The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour‐derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL‐6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development. Methods We investigated the interplay between activin A and IL‐6 in the cachexia‐inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL‐6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐bearing mice by a species‐specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy‐inducing activities, and muscle mass changes were evaluated in tumour‐bearing mice. Results We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL‐6 from cancer cells. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005). Conclusions Our data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.

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Section: Discussionmentioning

confidence: 94%

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Pettersen

Andersen

Veen

et al. 2019

J cachexia sarcopenia muscle

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“…Severe sepsis is often attributed to immune dysregulation, and the imbalance between pro-and anti-inflammatory cytokines may serve a crucial role in the pathogenesis of sepsis (17). Patients who express high levels of interleukin (IL)-6 have an increased risk of mortality (18,19). Although the combination of IL-6 and CRP plasma biomarkers may be helpful in sepsis diagnosis, recent studies demonstrated that IL-6 and CRP are not ideal as they lack sufficient sensitivity and specificity (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Identification of risk factors for sepsis-associated mortality by gene expression profiling analysis

Yan

Chen

et al. 2018

Mol Med Report

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Sepsis is a common cause of mortality due to systemic infection. Although numerous studies have investigated this life-threatening condition, there remains a lack of suitable markers to evaluate the severity of sepsis. The present study focused on the identification of risk factors for sepsis‑associated mortality by genome‑wide expression profiling. Initially, the GEO2R web tool was used to identify the differentially expressed genes (DEGs) between sepsis survivors and nonsurvivors. It was identified that the upregulated DEGs in the nonsurvivors compared with survivors were highly enriched in the type I interferon (IFN‑I) signaling pathway. Furthermore, the associations of the upregulated genes were analyzed by STRING and the results demonstrated that a set of proteins in IFN‑I signaling pathway closely interacted with each other. To further investigate whether the IFN‑I signaling pathway is dysregulated in a subset of patients with a high risk of mortality due to sepsis, in this case neonates, the DEGs between the cord blood mononuclear cells of neonates and adult peripheral blood mononuclear cells were analyzed. It was identified that DEGs were not enriched in IFN‑I signaling in the blood of untreated neonates and adults; however, IFN‑I signaling was upregulated in the lipopolysaccharide (LPS)‑treated cord blood mononuclear cells of healthy neonates compared with the LPS‑treated peripheral blood mononuclear cells of adults. In addition, these data revealed that the proteins involved in the IFN‑I signaling pathway possessed a higher number of interacting partners. These results indicated that upregulated IFN‑I signaling may be a high-risk factor for mortality due to sepsis.

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“…The effect of activin A on phagocytic activity of different phagocytes, mainly macrophages, monocytes [ 28 , 40 ], and neutrophils [ 47 ], has been addressed before; however, to our knowledge, this is the first study investigating the effect of activin A on phagocytic activity of microglial cells. Other groups examined phagocytosis of chicken red blood cells (cRBC), latex particles, and microspheres or pinocytosis of natural red, whereas we investigated phagocytosis of living bacteria.…”

Section: Discussionmentioning

confidence: 99%

Activin A increases phagocytosis of Escherichia coli K1 by primary murine microglial cells activated by toll-like receptor agonists

Diesselberg

Ribes

Seele

et al. 2018

J Neuroinflammation

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BackgroundBacterial meningitis is associated with high mortality and long-term neurological sequelae. Increasing the phagocytic activity of microglia could improve the resistance of the CNS against infections. We studied the influence of activin A, a member of the TGF-β family with known immunoregulatory and neuroprotective effects, on the functions of microglial cells in vitro.MethodsPrimary murine microglial cells were treated with activin A (0.13 ng/ml–13 μg/ml) alone or in combination with agonists of TLR2, 4, and 9. Phagocytosis of Escherichia coli K1 as well as release of TNF-α, IL-6, CXCL1, and NO was assessed.ResultsActivin A dose-dependently enhanced the phagocytosis of Escherichia coli K1 by microglial cells activated by agonists of TLR2, 4, and 9 without further increasing NO and proinflammatory cytokine release. Cell viability of microglial cells was not affected by activin A.ConclusionsPriming of microglial cells with activin A could increase the elimination of bacteria in bacterial CNS infections. This preventive strategy could improve the resistance of the brain to infections, particularly in elderly and immunocompromised patients.

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Activin A regulates activation of mouse neutrophils by Smad3 signalling

Cited by 22 publications

References 44 publications

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Identification of risk factors for sepsis-associated mortality by gene expression profiling analysis

Activin A increases phagocytosis of Escherichia coli K1 by primary murine microglial cells activated by toll-like receptor agonists

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