PMID- 9736697
OWN - NLM
STAT- MEDLINE
DCOM- 19981026
LR  - 20211203
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 95
IP  - 19
DP  - 1998 Sep 15
TI  - Rapid inhibition of interleukin-6 signaling and Stat3 activation mediated by 
      mitogen-activated protein kinases.
PG  - 11107-12
AB  - Gene activation and cellular differentiation induced by interleukin-6 (IL-6) and 
      transcription factor Stat3 are suppressed by several factors, including 
      ionomycin, granulocyte/macrophage-colony-stimulating factor, and phorbol 
      12-myristate 13-acetate (PMA), that block IL-6-induced Stat3 activation. These 
      inhibitory agents activate mitogen activated protein kinases (MAPKs), and thus 
      the role of MAPKs in the mechanism of inhibition of Stat3 activation was 
      investigated. Inhibition of IL-6-induced Stat3 activation by PMA and ionomycin 
      was rapid (within 5 min) and did not require new RNA or protein synthesis. 
      Inhibition of Stat3 DNA-binding activity and tyrosine phosphorylation by PMA, 
      ionomycin, and granulocyte/macrophage-colony-stimulating factor was reversed when 
      activation of the extracellular signal-regulated kinase (ERK) group of MAPKs was 
      blocked by using specific kinase inhibitors. Expression of constitutively active 
      MEK1, the kinase that activates ERKs, or overexpression of ERK2, but not JNK1, 
      inhibited Stat3 activation. Inhibition of Stat3 correlated with suppression of 
      IL-6-induction of a signal transducer and activator of transcription 
      (STAT)-dependent reporter gene. In contrast to IL-6, activation of Stat3 by 
      interferon-alpha was not inhibited. MEKs and ERKs inhibited IL-6 activation of 
      Stat3 harboring a mutation at serine-727, the major site for serine 
      phosphorylation, similar to inhibition of wild-type Stat3, and inhibited Janus 
      kinases Jak1 and Jak2 upstream of Stat3 in the Jak-STAT-signaling pathway. These 
      results demonstrate an ERK-mediated mechanism for inhibiting IL-6-induced 
      Jak-STAT signaling that is rapid and inducible, and thus differs from previously 
      described mechanisms for downmodulation of the Jak-STAT pathway. This inhibitory 
      pathway provides a molecular mechanism for the antagonism of Stat3-mediated IL-6 
      activity by factors that activate ERKs.
FAU - Sengupta, T K
AU  - Sengupta TK
AD  - Department of Medicine, Hospital for Special Surgery, Cornell University Graduate 
      School of Medical Sciences New York, NY 10021, USA.
FAU - Talbot, E S
AU  - Talbot ES
FAU - Scherle, P A
AU  - Scherle PA
FAU - Ivashkiv, L B
AU  - Ivashkiv LB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Butadienes)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Flavonoids)
RN  - 0 (Interleukin-6)
RN  - 0 (Nitriles)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Trans-Activators)
RN  - 0 (U 0126)
RN  - 56092-81-0 (Ionomycin)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
SB  - IM
MH  - Butadienes/pharmacology
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
MH  - Cell Line
MH  - DNA-Binding Proteins/analysis/*metabolism
MH  - Enzyme Activation/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Flavonoids/pharmacology
MH  - Genes, Reporter/genetics
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology
MH  - Interleukin-6/*pharmacology
MH  - Ionomycin/pharmacology
MH  - MAP Kinase Kinase 1
MH  - *Mitogen-Activated Protein Kinase Kinases
MH  - Nitriles/pharmacology
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism
MH  - STAT3 Transcription Factor
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Trans-Activators/*metabolism
MH  - Transfection/genetics
PMC - PMC21603
EDAT- 1998/09/16 00:00
MHDA- 1998/09/16 00:01
PMCR- 1999/03/15
CRDT- 1998/09/16 00:00
PHST- 1998/09/16 00:00 [pubmed]
PHST- 1998/09/16 00:01 [medline]
PHST- 1998/09/16 00:00 [entrez]
PHST- 1999/03/15 00:00 [pmc-release]
AID - 0947 [pii]
AID - 10.1073/pnas.95.19.11107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11107-12. doi: 
      10.1073/pnas.95.19.11107.