PMID- 15739188
OWN - NLM
STAT- MEDLINE
DCOM- 20050630
LR  - 20091119
IS  - 0894-1491 (Print)
IS  - 0894-1491 (Linking)
VI  - 50
IP  - 3
DP  - 2005 May
TI  - c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia.
PG  - 235-46
AB  - The activation and function of c-Jun N-terminal kinases (JNKs) were investigated 
      in primary microglia cultures from neonatal rat brain, which express all three 
      JNK isoforms. Lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), 
      and thrombin preparations induced a rapid and lasting activation of JNKs in the 
      cytoplasm. In the nucleus, the activation patterns were rather complex. In 
      untreated microglia, the small pool of nuclear JNKs was strongly activated, while 
      the high-affinity JNK substrate c-Jun was only weakly phosphorylated. Stimulation 
      with LPS increased the total amount of nuclear JNKs and the phosphorylation of 
      the transcription factor c-Jun. Levels of activated JNKs in the nucleus, however, 
      rapidly decreased. Analysis of the nuclear JNK isoforms revealed that the amount 
      of JNK1 declined, while JNK2 increased, and the weakly expressed JNK3 did not 
      vary. This observation suggests that JNK2 is mainly responsible for the 
      activation of c-Jun in this context. Upstream of JNKs, LPS induced a lasting 
      activation of the constitutively present JNK kinase MKK4. The function of JNKs in 
      LPS-triggered cellular reactions was investigated using SP600125 (0.5-5 microM), 
      a direct inhibitor of JNKs. Inhibition of JNKs reduced the LPS-induced metabolic 
      activity and induction of the AP-1 target genes cyclooxygenase-2 (Cox-2), 
      TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) 
      in response to LPS, while ERK1/2 and p38 alpha had a more pronounced effect on 
      LPS-induced cellular enlargement than JNKs. In summary, JNKs are essential 
      mediators of relevant pro-inflammatory functions in microglia with different 
      contributions of the JNK isoforms.
FAU - Waetzig, Vicki
AU  - Waetzig V
AD  - Institute of Pharmacology, University Hospital Kiel, 24105 Kiel, Germany.
FAU - Czeloth, Karen
AU  - Czeloth K
FAU - Hidding, Ute
AU  - Hidding U
FAU - Mielke, Kirsten
AU  - Mielke K
FAU - Kanzow, Moritz
AU  - Kanzow M
FAU - Brecht, Stephan
AU  - Brecht S
FAU - Goetz, Mario
AU  - Goetz M
FAU - Lucius, Ralph
AU  - Lucius R
FAU - Herdegen, Thomas
AU  - Herdegen T
FAU - Hanisch, Uwe-Karsten
AU  - Hanisch UK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Glia
JT  - Glia
JID - 8806785
RN  - 0 (Chemokines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.1.24 (Mitogen-Activated Protein Kinase 9)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Cell Nucleus/drug effects/enzymology
MH  - Cells, Cultured
MH  - Chemokines/metabolism
MH  - Cytoplasm/drug effects/enzymology
MH  - Encephalitis/chemically induced/*enzymology/physiopathology
MH  - Enzyme Activation/drug effects/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism/pharmacology
MH  - Gliosis/chemically induced/*enzymology/physiopathology
MH  - Inflammation Mediators/*metabolism
MH  - JNK Mitogen-Activated Protein Kinases/drug effects/*metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Microglia/drug effects/*enzymology
MH  - Mitogen-Activated Protein Kinase 8/metabolism
MH  - Mitogen-Activated Protein Kinase 9/metabolism
MH  - Proto-Oncogene Proteins c-jun/metabolism
MH  - Rats
MH  - Thrombin/pharmacology
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism/pharmacology
EDAT- 2005/03/02 09:00
MHDA- 2005/07/01 09:00
CRDT- 2005/03/02 09:00
PHST- 2005/03/02 09:00 [pubmed]
PHST- 2005/07/01 09:00 [medline]
PHST- 2005/03/02 09:00 [entrez]
AID - 10.1002/glia.20173 [doi]
PST - ppublish
SO  - Glia. 2005 May;50(3):235-46. doi: 10.1002/glia.20173.