PMID- 20145200
OWN - NLM
STAT- MEDLINE
DCOM- 20100520
LR  - 20101118
IS  - 1938-3673 (Electronic)
IS  - 0741-5400 (Linking)
VI  - 87
IP  - 5
DP  - 2010 May
TI  - Protein tyrosine phosphatase SHP-1 positively regulates TLR-induced IL-12p40 
      production in macrophages through inhibition of phosphatidylinositol 3-kinase.
PG  - 845-55
LID - 10.1189/jlb.0409289 [doi]
AB  - SHP-1 is a cytoplasm protein tyrosine phosphatase expressed primarily in 
      hematopoietic cells. In the immune system, SHP-1 plays critical roles in 
      regulation of many receptor-mediated signaling cascades, and SHP-1 deficiency in 
      mice causes spontaneous inflammation and autoimmunity. Here, we report a unique 
      requirement for SHP-1 in interleukin-12/23 p40 (IL-12p40) production in response 
      to Toll-like receptor (TLR) stimulation in macrophages. Bone marrow-derived 
      macrophages (BMDMs) lacking significant SHP-1 activity display a profound defect 
      in IL-12p40 synthesis in response to lipopolysaccharide, peptidoglycan, and 
      synthetic TLR ligands, while producing normal amounts of other proinflammatory 
      cytokines, such as TNFalpha and IL-6. Inhibition of SHP-1 function in wild-type 
      BMDMs decreases IL-12p40, and expression of functional SHP-1 protein in mutant 
      cells restores IL-12p40 production following TLR ligation. SHP-1 regulation of 
      IL-12p40 transcription requires both its catalytic activity and phosphotyrosine 
      binding by its N-terminal SH2 domain and is mediated via repression of, and 
      interaction with, phosphatidylinositol 3-kinase, without affecting c-Rel 
      activation. In contrast to normal NF-kappaB activation, SHP-1-defective 
      me(v)/me(v) macrophages display a defect in nucleosome remodeling at the IL-12p40 
      promoter, and phosphatidylinositol 3-kinase inhibition significantly restores 
      normal nucleosome remodeling in me(v)/me(v) macrophages. Thus, there is a 
      critical role for the tyrosine phosphatase activity of SHP-1 for induction of 
      IL-12p40 production in macrophages in response to TLR ligands, a novel mechanism 
      for host regulation of a specific proinflammatory cytokine important in both 
      innate and adaptive immunity.
FAU - Zhou, Delu
AU  - Zhou D
AD  - Program in Microbial Pathogenesis and Host Defense, University of California, San 
      Francisco, California, USA.
FAU - Collins, Cathleen A
AU  - Collins CA
FAU - Wu, Ping
AU  - Wu P
FAU - Brown, Eric J
AU  - Brown EJ
LA  - eng
PT  - Journal Article
DEP - 20100209
PL  - England
TA  - J Leukoc Biol
JT  - Journal of leukocyte biology
JID - 8405628
RN  - 0 (Interleukin-12 Subunit p40)
RN  - 0 (Toll-Like Receptors)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
RN  - EC 3.1.3.48 (Ptpn6 protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Separation
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Immunoprecipitation
MH  - Interleukin-12 Subunit p40/*biosynthesis/immunology
MH  - Macrophages/immunology/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phosphatidylinositol 3-Kinases/immunology/*metabolism
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6/immunology/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/immunology
MH  - Toll-Like Receptors/immunology/*metabolism
EDAT- 2010/02/11 06:00
MHDA- 2010/05/21 06:00
CRDT- 2010/02/11 06:00
PHST- 2010/02/11 06:00 [entrez]
PHST- 2010/02/11 06:00 [pubmed]
PHST- 2010/05/21 06:00 [medline]
AID - jlb.0409289 [pii]
AID - 10.1189/jlb.0409289 [doi]
PST - ppublish
SO  - J Leukoc Biol. 2010 May;87(5):845-55. doi: 10.1189/jlb.0409289. Epub 2010 Feb 9.