PMID- 10202148
OWN - NLM
STAT- MEDLINE
DCOM- 19990601
LR  - 20181113
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 7
DP  - 1999 Apr 1
TI  - Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3
      (Mkk3)-deficient mice.
PG  - 1845-57
AB  - The p38 mitogen-activated protein kinase (MAPK) pathway, like the c-Jun
      N-terminal kinase (JNK) MAPK pathway, is activated in response to cellular stress
      and inflammation and is involved in many fundamental biological processes. To
      study the role of the p38 MAPK pathway in vivo, we have used homologous
      recombination in mice to inactivate the Mkk3 gene, one of the two specific MAPK
      kinases (MAPKKs) that activate p38 MAPK. Mkk3(-/-) mice were viable and fertile; 
      however, they were defective in interleukin-12 (IL-12) production by macrophages 
      and dendritic cells. Interferon-gamma production following immunization with
      protein antigens and in vitro differentiation of naive T cells is greatly
      reduced, suggesting an impaired type I cytokine immune response. The effect of
      the p38 MAPK pathway on IL-12 expression is at least partly transcriptional,
      since inhibition of this pathway blocks IL-12 p40 promoter activity in macrophage
      cell lines and IL-12 p40 mRNA is reduced in MKK3-deficient mice. We conclude that
      the p38 MAP kinase, activated through MKK3, is required for the production of
      inflammatory cytokines by both antigen-presenting cells and CD4(+) T cells.
FAU - Lu, H T
AU  - Lu HT
AD  - Howard Hughes Medical Institute and Section of Immunobiology, Yale University
      School of Medicine, New Haven, CT 06520, USA.
FAU - Yang, D D
AU  - Yang DD
FAU - Wysk, M
AU  - Wysk M
FAU - Gatti, E
AU  - Gatti E
FAU - Mellman, I
AU  - Mellman I
FAU - Davis, R J
AU  - Davis RJ
FAU - Flavell, R A
AU  - Flavell RA
LA  - eng
GR  - CA58396/CA/NCI NIH HHS/United States
GR  - CA72009/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Inflammation Mediators)
RN  - 187348-17-0 (Interleukin-12)
RN  - 82115-62-6 (Interferon-gamma)
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 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 3)
RN  - EC 2.7.12.2 (Map2k3 protein, mouse)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - Antigen-Presenting Cells/enzymology/immunology
MH  - CD4-Positive T-Lymphocytes/enzymology/immunology
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
MH  - Cells, Cultured
MH  - Dendritic Cells/enzymology/immunology
MH  - Enzyme Activation
MH  - Gene Expression Regulation
MH  - In Vitro Techniques
MH  - Inflammation Mediators/metabolism
MH  - Interferon-gamma/biosynthesis
MH  - Interleukin-12/*biosynthesis/genetics
MH  - MAP Kinase Kinase 3
MH  - Macrophages, Peritoneal/enzymology/immunology
MH  - Mice
MH  - Mice, Knockout
MH  - *Mitogen-Activated Protein Kinase Kinases
MH  - *Mitogen-Activated Protein Kinases
MH  - Promoter Regions, Genetic
MH  - Protein-Serine-Threonine Kinases/*deficiency/genetics
MH  - Protein-Tyrosine Kinases/*deficiency/genetics
MH  - p38 Mitogen-Activated Protein Kinases
PMC - PMC1171270
EDAT- 1999/04/15 00:00
MHDA- 1999/04/15 00:01
CRDT- 1999/04/15 00:00
PHST- 1999/04/15 00:00 [pubmed]
PHST- 1999/04/15 00:01 [medline]
PHST- 1999/04/15 00:00 [entrez]
AID - 10.1093/emboj/18.7.1845 [doi]
PST - ppublish
SO  - EMBO J. 1999 Apr 1;18(7):1845-57. doi: 10.1093/emboj/18.7.1845.