PMID- 34548527
OWN - NLM
STAT- MEDLINE
DCOM- 20211230
LR  - 20240507
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 11
IP  - 1
DP  - 2021 Sep 21
TI  - Metformin selectively dampens the acute inflammatory response through an 
      AMPK-dependent mechanism.
PG  - 18721
LID - 10.1038/s41598-021-97441-x [doi]
LID - 18721
AB  - Metformin is a first-line drug in the treatment of type-2 diabetes mellitus 
      (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, 
      metformin has emerged as a potent inhibitor of the chronic inflammatory response 
      of macrophages. In particular, metformin treatment has been shown to reduce 
      expression of interleukin (IL-) 1beta during long-term exposure to the 
      pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in 
      reactive oxygen species (ROS), which decreases the levels of the 
      hypoxia-inducible factor (HIF) 1-alpha, and through enhanced expression of IL-10. 
      However, the effect of metformin on the acute inflammatory response, before 
      significant levels of ROS accumulate in the cell, has not been explored. Here, we 
      show that metformin alters the acute inflammatory response through its activation 
      of AMP-activated protein kinase (AMPK), but independently of HIF1-alpha and IL-10, in 
      primary macrophages and two macrophage-like cell lines. Thus, metformin changes 
      the acute and the chronic inflammatory response through fundamentally distinct 
      mechanisms. Furthermore, RNA-seq analysis reveals that metformin pretreatment 
      affects the levels of a large yet selective subset of inflammatory genes, 
      dampening the response to short-term LPS exposure and affecting a wide range of 
      pathways and biological functions. Taken together, these findings reveal an 
      unexpected complexity in the anti-inflammatory properties of this widely used 
      drug.
CI  - (c) 2021. The Author(s).
FAU - Postler, Thomas S
AU  - Postler TS
AUID- ORCID: 0000-0002-3558-9084
AD  - Department of Microbiology & Immunology, Vagelos College of Physicians & 
      Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.
FAU - Peng, Vincent
AU  - Peng V
AD  - Department of Microbiology & Immunology, Vagelos College of Physicians & 
      Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO, 63110, USA.
FAU - Bhatt, Dev M
AU  - Bhatt DM
AD  - Department of Microbiology & Immunology, Vagelos College of Physicians & 
      Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.
AD  - Amgen Research Oncology and Inflammation, South San Francisco, CA, 94080, USA.
FAU - Ghosh, Sankar
AU  - Ghosh S
AUID- ORCID: 0000-0002-3227-0588
AD  - Department of Microbiology & Immunology, Vagelos College of Physicians & 
      Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA. 
      sg2715@cumc.columbia.edu.
LA  - eng
GR  - R37 AI033443/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210921
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (IL10 protein, human)
RN  - 0 (IL1B protein, human)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 130068-27-8 (Interleukin-10)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.4.3 (Adenylate Kinase)
SB  - IM
MH  - Adenylate Kinase/*metabolism
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology/*therapeutic use
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics
MH  - Inflammation/*prevention & control
MH  - Interleukin-10/genetics
MH  - Interleukin-1beta/genetics
MH  - Lipopolysaccharides/pharmacology
MH  - Metformin/pharmacology/*therapeutic use
MH  - NF-kappa B/genetics
MH  - RNA, Messenger/genetics
MH  - Reactive Oxygen Species/metabolism
PMC - PMC8455559
COIS- The authors declare no competing interests.
EDAT- 2021/09/23 06:00
MHDA- 2021/12/31 06:00
PMCR- 2021/09/21
CRDT- 2021/09/22 06:32
PHST- 2020/08/05 00:00 [received]
PHST- 2021/08/25 00:00 [accepted]
PHST- 2021/09/22 06:32 [entrez]
PHST- 2021/09/23 06:00 [pubmed]
PHST- 2021/12/31 06:00 [medline]
PHST- 2021/09/21 00:00 [pmc-release]
AID - 10.1038/s41598-021-97441-x [pii]
AID - 97441 [pii]
AID - 10.1038/s41598-021-97441-x [doi]
PST - epublish
SO  - Sci Rep. 2021 Sep 21;11(1):18721. doi: 10.1038/s41598-021-97441-x.