PMID- 26208884
OWN - NLM
STAT- MEDLINE
DCOM- 20160531
LR  - 20181113
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Print)
IS  - 0898-6568 (Linking)
VI  - 27
IP  - 10
DP  - 2015 Oct
TI  - MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 
      production in bone marrow derived macrophages.
PG  - 2068-76
LID - S0898-6568(15)00212-0 [pii]
LID - 10.1016/j.cellsig.2015.07.015 [doi]
AB  - The mitogen activated protein kinases ERK1/2 play an important role in response 
      to toll like receptor (TLR) activation and cytokine production, including IL-10 
      and IL-12. Here, we examined the role of MEK1 in ERK1/2 activation in response to 
      TLR4 agonist by using bone marrow-derived macrophages (BMDMs) from wild type (WT) 
      and Mek1(d/d)Sox2(Cre) mice. Our data demonstrates that MEK1 is essential for 
      ERK1/2 activation in response to LPS. Furthermore, stimulation of the TLR4 
      receptor of BMDMs derived from Mek1(d/d)Sox2(Cre) mice showed enhanced STAT4 
      phosphorylation and increased IL-12 secretion, but exhibited a significantly 
      lower IL-10 production as compared to WT macrophages. Most interestingly, TLR 
      ligation in the presence of recombinant IL-10 (rIL-10) or retinoic acid (RA) led 
      to ERK1/2 activation independent of MEK1 in BMDMs derived from Mek1(d/d)Sox2(Cre) 
      mice and led to inhibition of STAT4 and decreased IL-12 levels. Collectively, 
      these data suggest that MEK1 is required for TLR4 mediated ERK activation and in 
      turn regulates the production of IL-10 and IL-12. It also indicates that ERK1/2 
      can be activated independent of MEK1 in the presence of IL-10 and RA and this 
      activation negatively regulates IL-12, but positively regulates IL-10 production. 
      These findings may have significant implications for the development of drugs 
      that modulate MEK1 activity in the treatment of inflammatory, autoimmune and 
      proliferative diseases such as cancer.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Bouhamdan, Mohamad
AU  - Bouhamdan M
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 
      48201, USA.
FAU - Bauerfeld, Christian
AU  - Bauerfeld C
AD  - Department of Pediatrics, Division of Critical Care, Wayne State University 
      School of Medicine and Children's Hospital of Michigan, Detroit, MI 48201, USA.
FAU - Talreja, Jaya
AU  - Talreja J
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 
      48201, USA.
FAU - Beuret, Laurent
AU  - Beuret L
AD  - Centre de Recherche sur le Cancer de l'Universite Laval, CRCHU de Quebec, 
      L'Hotel-Dieu de Quebec, Quebec, Canada.
FAU - Charron, Jean
AU  - Charron J
AD  - Centre de Recherche sur le Cancer de l'Universite Laval, CRCHU de Quebec, 
      L'Hotel-Dieu de Quebec, Quebec, Canada.
FAU - Samavati, Lobelia
AU  - Samavati L
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 
      48201, USA; Center for Molecular Medicine and Genetics, Wayne State University 
      School of Medicine, Detroit, MI 48201, USA. Electronic address: 
      lsamavat@med.wayne.edu.
LA  - eng
GR  - R01 HL113508/HL/NHLBI NIH HHS/United States
GR  - R01HL113508/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150721
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (IL10 protein, mouse)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (STAT4 Transcription Factor)
RN  - 0 (Stat4 protein, mouse)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - 130068-27-8 (Interleukin-10)
RN  - 187348-17-0 (Interleukin-12)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (Map2k1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Enzyme Activation
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Interleukin-10/*biosynthesis
MH  - Interleukin-12/*biosynthesis
MH  - Lipopolysaccharides/pharmacology
MH  - MAP Kinase Kinase 1/*physiology
MH  - MAP Kinase Signaling System
MH  - Macrophages/*enzymology/immunology
MH  - Mice, 129 Strain
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational
MH  - STAT4 Transcription Factor/metabolism
MH  - Toll-Like Receptor 4/metabolism
MH  - Tretinoin/pharmacology
PMC - PMC4540637
MID - NIHMS712855
OTO - NOTNLM
OT  - ERK
OT  - IL-10
OT  - IL-12
OT  - MEK1
OT  - MEK2
OT  - Macrophages
OT  - STAT/JAK
EDAT- 2015/07/26 06:00
MHDA- 2016/06/01 06:00
PMCR- 2016/10/01
CRDT- 2015/07/26 06:00
PHST- 2015/04/21 00:00 [received]
PHST- 2015/06/24 00:00 [revised]
PHST- 2015/07/13 00:00 [accepted]
PHST- 2015/07/26 06:00 [entrez]
PHST- 2015/07/26 06:00 [pubmed]
PHST- 2016/06/01 06:00 [medline]
PHST- 2016/10/01 00:00 [pmc-release]
AID - S0898-6568(15)00212-0 [pii]
AID - 10.1016/j.cellsig.2015.07.015 [doi]
PST - ppublish
SO  - Cell Signal. 2015 Oct;27(10):2068-76. doi: 10.1016/j.cellsig.2015.07.015. Epub 
      2015 Jul 21.