PMID- 19741199
OWN - NLM
STAT- MEDLINE
DCOM- 20091117
LR  - 20211020
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 297
IP  - 5
DP  - 2009 Nov
TI  - Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell 
      activation.
PG  - C1294-306
LID - 10.1152/ajpcell.00160.2009 [doi]
AB  - The cholinergic anti-inflammatory pathway is a physiological mechanism that 
      inhibits cytokine production and minimizes tissue injury during inflammation. 
      Previous investigations revealed that cholinergic stimulation (via cholinergic 
      agonists and vagus nerve stimulation) suppresses endothelial cell activation and 
      leukocyte recruitment. The purpose of this study was to investigate the 
      mechanisms by which cholinergic agonists (e.g., nicotine and GTS-21) regulate 
      endothelial cell activation. Specifically, we examined the effects of cholinergic 
      agonists on IL-6-mediated endothelial cell activation through the JAK2/STAT3 
      signaling pathway. Treatment of macrovascular human umbilical vein endothelial 
      cells (HUVECs) and microvascular endothelial cells (MVECs) with the cholinergic 
      agonists nicotine and GTS-21 significantly reduced IL-6-mediated monocyte 
      chemoattractant protein-1 (MCP-1) production and ICAM-1 expression which are 
      regulated through the JAK2/STAT3 pathway. We found that treatment of endothelial 
      cells with cholinergic agonists significantly reduced STAT3 activation by 
      phosphorylation and DNA binding. The inhibition of STAT3 phosphorylation was 
      reversed by sodium orthovanadate, an inhibitor of tyrosine phosphatases, as well 
      as by NSC-87877 suggesting a SHP1/2-dependent mechanism. Further investigations 
      showed that cholinergic agonists reduced the phosphorylation of JAK2, an upstream 
      component of the JAK2/STAT3 pathway. Finally, we observed that nicotine and 
      GTS-21 treatment decreased levels of SOCS3 (suppressor of cytokine signaling; a 
      regulator of the inflammatory activity of IL-6) in activated endothelial cells. 
      These data demonstrate that cholinergic agonists suppress IL-6-mediated 
      endothelial cell activation through the JAK2/STAT3 pathway. Our results have 
      significant implications for better understanding the therapeutic potential of 
      cholinergic agonists for treating IL-6 mediated inflammatory conditions.
FAU - Chatterjee, Prodyot K
AU  - Chatterjee PK
AD  - The Center for Immunology and Inflammation, The Feinstein Institute for Medical 
      Research, Manhasset, New York, USA.
FAU - Al-Abed, Yousef
AU  - Al-Abed Y
FAU - Sherry, Barbara
AU  - Sherry B
FAU - Metz, Christine N
AU  - Metz CN
LA  - eng
GR  - R01 GM070727-03/GM/NIGMS NIH HHS/United States
GR  - R01 GM070727-04/GM/NIGMS NIH HHS/United States
GR  - R01 AI-059742/AI/NIAID NIH HHS/United States
GR  - R01 GM070727-02/GM/NIGMS NIH HHS/United States
GR  - R01 GM-070727/GM/NIGMS NIH HHS/United States
GR  - R01 GM070727/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090909
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Benzylidene Compounds)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (Nicotinic Agonists)
RN  - 0 (Pyridines)
RN  - 0 (SOCS3 protein, human)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Suppressor of Cytokine Signaling 3 Protein)
RN  - 0 (Suppressor of Cytokine Signaling Proteins)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - 6M3C89ZY6R (Nicotine)
RN  - 8S399XDN2K (3-(2,4-dimethoxybenzylidene)anabaseine)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Benzylidene Compounds/pharmacology
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Chemokine CCL2/drug effects/metabolism
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Humans
MH  - Intercellular Adhesion Molecule-1/drug effects/metabolism
MH  - Interleukin-6/metabolism
MH  - Janus Kinase 2/drug effects/*metabolism
MH  - Nicotine/pharmacology
MH  - Nicotinic Agonists/*pharmacology
MH  - Phosphorylation/drug effects
MH  - Pyridines/pharmacology
MH  - STAT3 Transcription Factor/drug effects/*metabolism
MH  - Signal Transduction/drug effects/*physiology
MH  - Suppressor of Cytokine Signaling 3 Protein
MH  - Suppressor of Cytokine Signaling Proteins/drug effects/metabolism
PMC - PMC2777398
EDAT- 2009/09/11 06:00
MHDA- 2009/11/18 06:00
PMCR- 2010/11/01
CRDT- 2009/09/11 06:00
PHST- 2009/09/11 06:00 [entrez]
PHST- 2009/09/11 06:00 [pubmed]
PHST- 2009/11/18 06:00 [medline]
PHST- 2010/11/01 00:00 [pmc-release]
AID - 00160.2009 [pii]
AID - C-00160-2009 [pii]
AID - 10.1152/ajpcell.00160.2009 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2009 Nov;297(5):C1294-306. doi: 
      10.1152/ajpcell.00160.2009. Epub 2009 Sep 9.