Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Tsuei, An‐Chi; Martinus, Ryan Dennis

doi:10.1007/s12192-011-0282-6

Cited by 8 publications

(6 citation statements)

References 20 publications

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“…However, anti-TLR2 Ab was able to inhibit almost 70% of the IL-10 produced by the control group treated with isotype control Ab. This indicates a predominant role of the TLR2 receptors in triggering IL-10 production by Mtbhsp60 even in a surrogate cell line like THP-1, which was used frequently by several groups (29,82,83). The data obtained by using macrophages from the TLR2 as well as TLR4 knock-out mice once again support our findings that Mtbhsp60 predominantly targets the TLR2 receptors to induce IL-10 cytokine.…”

Section: Discussionsupporting

confidence: 86%

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

Parveen

Varman

Nair

et al. 2013

Journal of Biological Chemistry

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Background: Mtbhsp60 induces TLR2-mediated anti-inflammatory response in macrophages, but the mechanisms are not well understood. Results: Clathrin-dependent TLR2-mediated endocytosis of Mtbhsp60 is required to induce anti-inflammatory response via p38 MAPK activation. Conclusion: Mtbhsp60 induces anti-inflammatory response upon endocytosis. Blockage of endocytosis predominantly leads to pro-inflammatory cytokine production. Significance: This information is important to tailor the Mtbhsp60-triggered IL-10 signaling to specifically block the excess nonprotective Th2-type response.

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Section: Discussionsupporting

confidence: 86%

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

Parveen

Varman

Nair

et al. 2013

Journal of Biological Chemistry

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“…The extraction of cellular protein, SDS-PAGE and Western blot analysis was carried out as described in Tsuei and Martinus (2012). Briefly, total cellular protein was extracted using the TENT buffer (50 mM Tris, 250 mM NaCl, 5 mM EDTA, 1% Triton X-100 and freshly supplemented with 0.4 mM phenlymethylsulfonyl fluoride).…”

Section: Protein Extraction and Western Blot Analysismentioning

confidence: 99%

Endothelial TNF-α induction by Hsp60 secreted from THP-1 monocytes exposed to hyperglycaemic conditions

Martinus

Goldsbury

2018

Cell Stress and Chaperones

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A non-resolving inflammation of the endothelium is recognised to be an important process leading to atherosclerosis. In diabetes, this process is thought to account for a significant number of cardiovascular disease-associated death and disability. However, the molecular mechanisms by which diabetes contributes to endothelial inflammation remain to be established. Whilst there is some evidence linking hyperglycaemia-induced reactive oxygen species (ROS) formation by the mitochondrial electron-transport chain to oxidative stress, cellular injury and apoptosis in the endothelium, a clear link to endothelium inflammation has not yet been established. The mitochondrial molecular stress protein Hsp60 is known to be secreted from mammalian cells and is capable of activating pro-inflammatory mediators on target cells expressing Toll-like receptors (TLRs). Hsp60 is also known to be elevated in serum of diabetes patients and has been shown to be upregulated by hyperglycaemic growth conditions in cultured human HeLa cells. This study shows that Hsp60 induced in human acute monocyte leukaemia cell line (THP-1) cells grown under hyperglycaemic conditions (25 mM glucose) was able to be secreted into growth media. Furthermore, the secretion of Hsp60 from THP-1 cells was able to be inhibited by 5,5-(N-N-dimethyl)-amiloride hydrochloride (DMA), an exosomal inhibitor. Interestingly, the conditioned media obtained from THP-1 cells grown in the presence of 25 mM glucose was able to induce the secretion of TNF-α in human vascular endothelium cell line (HUVEC). When conditioned media was immuno-depleted of Hsp60, there was a significant reduction in the release of TNF-α from the HUVEC cells. This suggests that a potential link may exist between hyperglycaemia-induced expression of Hsp60 in monocyte cells and vascular inflammation. Circulating levels of Hsp60 due to mitochondrial stress in diabetes patients could therefore be an important modulator of inflammation in endothelial cells and thus contribute to the increased incidences of atherosclerosis in diabetes mellitus.

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“…Finally, the enrichment of antigen processing and presentation pathway and significantly reduced expression of genes coding for the cluster of differentiation 14 (CD14), which was already proved to be differentially expressed in metformin-treated monocyte cells, and the cluster of differentiation 163 (CD163) [47], a scavenger receptor which has been previously associated with insulin resistance in patients with T2DM, altogether may explain well-known participation of metformin in the inflammatory and immune responses [48].…”

Section: Plos Onementioning

confidence: 95%

Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response

et al. 2020

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Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c � 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log 2 FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.

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Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Cited by 8 publications

References 20 publications

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

Endothelial TNF-α induction by Hsp60 secreted from THP-1 monocytes exposed to hyperglycaemic conditions

Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response

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