PMID- 25697779
OWN - NLM
STAT- MEDLINE
DCOM- 20160314
LR  - 20181113
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 83
DP  - 2015 Jun
TI  - MKK3 mediates inflammatory response through modulation of mitochondrial function.
PG  - 139-48
LID - S0891-5849(15)00077-5 [pii]
LID - 10.1016/j.freeradbiomed.2015.01.035 [doi]
AB  - Mitochondria are increasingly recognized as drivers of inflammatory responses. 
      MAP kinase kinase 3 (MKK3), a dual-specificity protein kinase, is activated in 
      inflammation and in turn activates p38 MAP kinase signaling. Here we show that 
      MKK3 influences mitochondrial function and acts as a critical mediator of 
      inflammation. MKK3-deficient (MKK3(-/-)) mice and bone marrow-derived macrophages 
      (BMDMs) secreted smaller amounts of cytokines than wild type (WT) after 
      lipopolysaccharide (LPS) exposure. There was improved mitochondrial function, as 
      measured by basal oxygen consumption rate, mitochondrial membrane potential, and 
      ATP production, in MKK3(-/-) BMDMs. After LPS exposure, MKK3(-/-) BMDMs did not 
      show a significant increase in cellular reactive oxygen species production or in 
      mitochondrial superoxide compared to WT. Activation of two important inflammatory 
      mediators, i.e., the nuclear translocation of NF-kappaB and caspase-1 activity (a key 
      component of the inflammasome), was lower in MKK3(-/-) BMDMs. p38 and JNK 
      activation was lower in MKK3(-/-) BMDMs compared to WT after exposure to LPS. 
      Knockdown of MKK3 by siRNA in wild-type BMDMs improved mitochondrial membrane 
      potential, reduced LPS-induced caspase-1 activation, and attenuated cytokine 
      secretion. Our studies establish MKK3 as a regulator of mitochondrial function 
      and inflammatory responses to LPS and suggest that MKK3 may be a therapeutic 
      target in inflammatory disorders such as sepsis.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Srivastava, Anup
AU  - Srivastava A
AD  - Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, 
      Yale University School of Medicine, New Haven, CT 06520-8057, USA.
FAU - Shinn, Amanda S
AU  - Shinn AS
AD  - Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, 
      Yale University School of Medicine, New Haven, CT 06520-8057, USA.
FAU - Lee, Patty J
AU  - Lee PJ
AD  - Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, 
      Yale University School of Medicine, New Haven, CT 06520-8057, USA.
FAU - Mannam, Praveen
AU  - Mannam P
AD  - Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, 
      Yale University School of Medicine, New Haven, CT 06520-8057, USA. Electronic 
      address: praveen.mannam@yale.edu.
LA  - eng
GR  - R01 HL071595/HL/NHLBI NIH HHS/United States
GR  - R01HL071595/HL/NHLBI NIH HHS/United States
GR  - R03AG042358-02/AG/NIA NIH HHS/United States
GR  - R01 HL090660/HL/NHLBI NIH HHS/United States
GR  - R01HL090660/HL/NHLBI NIH HHS/United States
GR  - P30 AG021342/AG/NIA NIH HHS/United States
GR  - P30AG021342/AG/NIA NIH HHS/United States
GR  - R03 AG042358/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150217
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 3)
RN  - EC 2.7.12.2 (Map2k3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Bone Marrow/drug effects/*immunology/metabolism
MH  - Cells, Cultured
MH  - Cytokines/metabolism
MH  - Inflammation/*immunology/metabolism/pathology
MH  - Lipopolysaccharides/pharmacology
MH  - MAP Kinase Kinase 3/antagonists & inhibitors/*physiology
MH  - Macrophages/drug effects/*immunology/metabolism
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mitochondria/drug effects/*immunology/metabolism
MH  - Phosphorylation/drug effects
MH  - RNA, Small Interfering/genetics
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/drug effects
PMC - PMC4441852
MID - NIHMS665128
OTO - NOTNLM
OT  - Acute lung injury
OT  - Caspase 1
OT  - Free radicals
OT  - Inflammasome
OT  - Inflammation
OT  - Mitochondria
OT  - NF-kappaB
OT  - Oxidants
OT  - Sepsis
COIS- Author Disclosure Statement No conflicts of interest, financial or otherwise, are 
      declared by the author(s).
EDAT- 2015/02/24 06:00
MHDA- 2016/03/15 06:00
PMCR- 2016/06/01
CRDT- 2015/02/21 06:00
PHST- 2014/12/30 00:00 [received]
PHST- 2015/01/23 00:00 [revised]
PHST- 2015/01/23 00:00 [accepted]
PHST- 2015/02/21 06:00 [entrez]
PHST- 2015/02/24 06:00 [pubmed]
PHST- 2016/03/15 06:00 [medline]
PHST- 2016/06/01 00:00 [pmc-release]
AID - S0891-5849(15)00077-5 [pii]
AID - 10.1016/j.freeradbiomed.2015.01.035 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2015 Jun;83:139-48. doi: 
      10.1016/j.freeradbiomed.2015.01.035. Epub 2015 Feb 17.