PMID- 27781339
OWN - NLM
STAT- MEDLINE
DCOM- 20180215
LR  - 20181202
IS  - 1365-2982 (Electronic)
IS  - 1350-1925 (Print)
IS  - 1350-1925 (Linking)
VI  - 29
IP  - 4
DP  - 2017 Apr
TI  - Tumor necrosis factor alpha derived from classically activated "M1" macrophages 
      reduces interstitial cell of Cajal numbers.
LID - 10.1111/nmo.12984 [doi]
AB  - BACKGROUND: Delayed gastric emptying in diabetic mice and humans is associated 
      with changes in macrophage phenotype and loss of interstitial cells of Cajal 
      (ICC) in the gastric muscle layers. In diabetic mice, classically activated M1 
      macrophages are associated with delayed gastric emptying, whereas alternatively 
      activated M2 macrophages are associated with normal gastric emptying. This study 
      aimed to determine if secreted factors from M1 macrophages could injure mouse ICC 
      in primary culture. METHODS: Cultures of gastric ICC were treated with 
      conditioned medium (CM) from activated bone marrow-derived macrophages (BMDMs) 
      and the effect of CM was quantified by counting ICC per high-powered field. KEY 
      RESULTS: Bone marrow-derived macrophages were activated to a M1 or M2 phenotype 
      confirmed by qRT-PCR. Conditioned medium from M1 macrophages reduced ICC numbers 
      by 41.1%, whereas M2-CM had no effect as compared to unconditioned, control 
      media. Immunoblot analysis of 40 chemokines/cytokines found 12 that were 
      significantly increased in M1-CM, including tumor necrosis factor alpha (TNF-alpha). 
      ELISA detected 0.697+/-0.03 ng mL(-1) TNF-alpha in M1-CM. Recombinant mouse TNF-alpha 
      reduced Kit expression and ICC numbers in a concentration-dependent manner 
      (EC50 = 0.817 ng mL(-1) ). Blocking M1-CM TNF-alpha with a neutralizing antibody 
      preserved ICC numbers. The caspase inhibitor Z-VAD.fmk partly preserved ICC 
      numbers (cells/field; 6.63+/-1.04, 9.82+/-1.80 w/Z-VAD.fmk, n=6, P<.05). CONCLUSIONS 
      & INFERENCES: This work demonstrates that TNF-alpha secreted from M1 macrophages can 
      result in Kit loss and directly injure ICC in vitro partly through 
      caspase-dependent apoptosis and may play an important role in ICC depletion in 
      diabetic gastroparesis.
CI  - (c) 2016 John Wiley & Sons Ltd.
FAU - Eisenman, S T
AU  - Eisenman ST
AD  - Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
FAU - Gibbons, S J
AU  - Gibbons SJ
AD  - Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
FAU - Verhulst, P-J
AU  - Verhulst PJ
AD  - Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
FAU - Cipriani, G
AU  - Cipriani G
AD  - Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
FAU - Saur, D
AU  - Saur D
AD  - Department of Internal Medicine II, Klinikum rechts der Isar, Technische 
      Universitat Munchen, Munchen, Germany.
FAU - Farrugia, G
AU  - Farrugia G
AD  - Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA.
LA  - eng
GR  - P01 DK068055/DK/NIDDK NIH HHS/United States
GR  - P30 DK084567/DK/NIDDK NIH HHS/United States
GR  - R01 DK057061/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20161025
PL  - England
TA  - Neurogastroenterol Motil
JT  - Neurogastroenterology and motility
JID - 9432572
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Cell Count/methods
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Gene Knock-In Techniques
MH  - Interstitial Cells of Cajal/drug effects/*metabolism
MH  - Macrophages/*metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Tumor Necrosis Factor-alpha/*metabolism/pharmacology
PMC - PMC5367986
MID - NIHMS821183
OTO - NOTNLM
OT  - caspase-mediated apoptosis
OT  - cell death
OT  - cytokines
OT  - diabetic gastroparesis
OT  - gastrointestinal motility
EDAT- 2016/10/27 06:00
MHDA- 2018/02/16 06:00
PMCR- 2018/04/01
CRDT- 2016/10/27 06:00
PHST- 2016/05/09 00:00 [received]
PHST- 2016/09/20 00:00 [revised]
PHST- 2016/09/28 00:00 [accepted]
PHST- 2016/10/27 06:00 [pubmed]
PHST- 2018/02/16 06:00 [medline]
PHST- 2016/10/27 06:00 [entrez]
PHST- 2018/04/01 00:00 [pmc-release]
AID - 10.1111/nmo.12984 [doi]
PST - ppublish
SO  - Neurogastroenterol Motil. 2017 Apr;29(4):10.1111/nmo.12984. doi: 
      10.1111/nmo.12984. Epub 2016 Oct 25.