PMID- 21422245
OWN - NLM
STAT- MEDLINE
DCOM- 20110705
LR  - 20220309
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 186
IP  - 9
DP  - 2011 May 1
TI  - IL-6 production is positively regulated by two distinct Src homology domain 
      2-containing tyrosine phosphatase-1 (SHP-1)-dependent CCAAT/enhancer-binding 
      protein beta and NF-kappaB pathways and an SHP-1-independent NF-kappaB pathway in 
      lipopolysaccharide-stimulated bone marrow-derived macrophages.
PG  - 5443-56
LID - 10.4049/jimmunol.1003551 [doi]
AB  - Comparison of the inflammatory cytokine profile in bone marrow-derived 
      macrophages (BMDMs) from normal and Src homology domain 2-containing tyrosine 
      phosphatase-1 (SHP-1)-deficient Motheaten (me/me) mice revealed a dramatic 
      suppression of IL-6 transcript and protein in me/me BMDMs after LPS stimulation. 
      Interfering with SHP-1 expression using antisense SHP-1 oligonucleotides led to a 
      significant downregulation of IL-6 in normal BMDMs. Conversely, reconstitution of 
      me/me BMDMs with the SHP-1 gene using adenoviral vectors restored IL-6 
      production. Expression of only SHP-1 Src homology region 2 domains in normal 
      BMDMs inhibited IL-6 production, confirming that IL-6 regulation depends on SHP-1 
      phosphatase activity. We further demonstrated that loss of SHP-1 function affects 
      proper phosphorylation of Erk1/2 MAPKs and, to a lesser degree, of NF-kappaB 
      downstream of TLR4 in BMDMs. Inefficient phosphorylation of Erk1/2 MAPKs 
      abrogated the activation of C/EBPbeta transcription factor, which was reversed on 
      restoration of SHP-1 function and led to a concomitant enhancement of IL-6 
      production. We demonstrate that IL-6 production is regulated by a complex network 
      of signaling pathways that include SHP-1-dependent activation of Erk1/2-C/EBPbeta 
      and NF-kappaB, in addition to SHP-1-independent IkappaB pathway through the activation of 
      protein tyrosine kinases downstream of TLR4. Taken together, these results 
      revealed for the first time, to our knowledge, a positive and critical role of 
      SHP-1 in IL-6 regulation and dependence of Erk1/2-C/EBPbeta pathway in addition to 
      that of IkappaB on SHP-1 activity required for IL-6 induction after LPS stimulation.
FAU - Rego, Dorothy
AU  - Rego D
AD  - Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, 
      University of Ottawa, Ottawa, Ontario KIH 8M5, Canada.
FAU - Kumar, Ashok
AU  - Kumar A
FAU - Nilchi, Ladan
AU  - Nilchi L
FAU - Wright, Kathryn
AU  - Wright K
FAU - Huang, Stephen
AU  - Huang S
FAU - Kozlowski, Maya
AU  - Kozlowski M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110321
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (CCAAT-Enhancer-Binding Protein-beta)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
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  - Blotting, Western
MH  - Bone Marrow Cells/immunology/metabolism
MH  - CCAAT-Enhancer-Binding Protein-beta/immunology/*metabolism
MH  - Cell Separation
MH  - Cytokines/biosynthesis
MH  - Electrophoretic Mobility Shift Assay
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Gene Expression
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation/*immunology
MH  - Interleukin-6/*biosynthesis/genetics/immunology
MH  - Lipopolysaccharides/immunology
MH  - Macrophages/*immunology/metabolism
MH  - Mice
MH  - Mice, Mutant Strains
MH  - NF-kappa B/immunology/*metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6/immunology/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/immunology
MH  - Up-Regulation
EDAT- 2011/03/23 06:00
MHDA- 2011/07/06 06:00
CRDT- 2011/03/23 06:00
PHST- 2011/03/23 06:00 [entrez]
PHST- 2011/03/23 06:00 [pubmed]
PHST- 2011/07/06 06:00 [medline]
AID - jimmunol.1003551 [pii]
AID - 10.4049/jimmunol.1003551 [doi]
PST - ppublish
SO  - J Immunol. 2011 May 1;186(9):5443-56. doi: 10.4049/jimmunol.1003551. Epub 2011 
      Mar 21.