The immunomodulatory effects of metformin in LPS-induced macrophages : an in vitro study
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG..
OBJECTIVE: The study aimed to explore the immunomodulatory effects of clinically relevant concentrations of metformin on macrophages during sepsis, which is characterized by an initial hyperinflammatory phase followed by a period of immunosuppression. METHODS: We employed the RAW 264.7 mouse macrophage cell line as an in vitro model to induce inflammatory responses and immune suppression through primary and secondary stimulation by lipopolysaccharide (LPS). The cells were exposed to clinically relevant concentrations of metformin, and their responses were gauged through cytotoxicity assays, enzyme-linked immunosorbent assay for cytokine quantification, and assessments of intracellular reactive oxygen species (ROS) production. Moreover, to probe the role of AMPK in mediating the effects of metformin, we conducted an AMP-activated protein kinase (AMPK) activity assay and knocked down AMPK using siRNA. RESULTS: Our study revealed that clinically relevant concentrations of metformin considerably decreased the LPS-induced secretion of tumor necrosis factor-α and interleukin-6, which indicates the suppression of the initial hyperinflammatory response. Furthermore, metformin prevented LPS-induced immunosuppression. Notably, these immunomodulatory effects of metformin were not mediated by the activation of the AMPK pathway, as evidenced by the unaltered AMPK activity and siRNA experiments. The modulation of intracellular ROS levels emerged as the critical mechanism underlying the inhibition of hyperinflammation and impediment of immunosuppression by metformin.
CONCLUSION: A certain therapeutic dose of metformin inhibited hyperinflammatory responses and alleviated immunosuppression in LPS-induced macrophages through the bidirectional modulation of intracellular ROS generation.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:73 |
|---|---|
| Enthalten in: |
Inflammation research : official journal of the European Histamine Research Society ... [et al. - 73(2024), 2 vom: 13. Jan., Seite 175-181 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Wang, Zhiyong [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 31.01.2024 Date Revised 31.01.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s00011-023-01827-8 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM365817422 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM365817422 | ||
| 003 | DE-627 | ||
| 005 | 20240131232002.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s00011-023-01827-8 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1276.xml |
| 035 | |a (DE-627)NLM365817422 | ||
| 035 | |a (NLM)38091014 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Wang, Zhiyong |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The immunomodulatory effects of metformin in LPS-induced macrophages |b an in vitro study |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 31.01.2024 | ||
| 500 | |a Date Revised 31.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG. | ||
| 520 | |a OBJECTIVE: The study aimed to explore the immunomodulatory effects of clinically relevant concentrations of metformin on macrophages during sepsis, which is characterized by an initial hyperinflammatory phase followed by a period of immunosuppression. METHODS: We employed the RAW 264.7 mouse macrophage cell line as an in vitro model to induce inflammatory responses and immune suppression through primary and secondary stimulation by lipopolysaccharide (LPS). The cells were exposed to clinically relevant concentrations of metformin, and their responses were gauged through cytotoxicity assays, enzyme-linked immunosorbent assay for cytokine quantification, and assessments of intracellular reactive oxygen species (ROS) production. Moreover, to probe the role of AMPK in mediating the effects of metformin, we conducted an AMP-activated protein kinase (AMPK) activity assay and knocked down AMPK using siRNA. RESULTS: Our study revealed that clinically relevant concentrations of metformin considerably decreased the LPS-induced secretion of tumor necrosis factor-α and interleukin-6, which indicates the suppression of the initial hyperinflammatory response. Furthermore, metformin prevented LPS-induced immunosuppression. Notably, these immunomodulatory effects of metformin were not mediated by the activation of the AMPK pathway, as evidenced by the unaltered AMPK activity and siRNA experiments. The modulation of intracellular ROS levels emerged as the critical mechanism underlying the inhibition of hyperinflammation and impediment of immunosuppression by metformin | ||
| 520 | |a CONCLUSION: A certain therapeutic dose of metformin inhibited hyperinflammatory responses and alleviated immunosuppression in LPS-induced macrophages through the bidirectional modulation of intracellular ROS generation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Immunosuppression | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Lipopolysaccharide | |
| 650 | 4 | |a Macrophage | |
| 650 | 4 | |a Metformin | |
| 650 | 7 | |a Metformin |2 NLM | |
| 650 | 7 | |a 9100L32L2N |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a AMP-Activated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.31 |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 700 | 1 | |a Wang, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Mao |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Pei |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Inflammation research : official journal of the European Histamine Research Society ... [et al. |d 1997 |g 73(2024), 2 vom: 13. Jan., Seite 175-181 |w (DE-627)NLM075208601 |x 1420-908X |7 nnns |
| 773 | 1 | 8 | |g volume:73 |g year:2024 |g number:2 |g day:13 |g month:01 |g pages:175-181 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00011-023-01827-8 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 73 |j 2024 |e 2 |b 13 |c 01 |h 175-181 | ||