PMID- 16571868
OWN - NLM
STAT- MEDLINE
DCOM- 20060912
LR  - 20200930
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 291
IP  - 3
DP  - 2006 Sep
TI  - Src family kinases regulate p38 MAPK-mediated IL-6 production in Kupffer cells 
      following hypoxia.
PG  - C476-82
AB  - Tissue hypoxia is a common sequel of trauma-hemorrhage but can occur even without 
      blood loss under hypoxic conditions. Although hypoxia is known to upregulate 
      Kupffer cells (KC) to release cytokines, the precise mechanism of release remains 
      unknown. We hypothesized that Src family kinases play a role in mediating KC 
      mitogen-activated protein kinase (MAPK) signaling and their cytokine production 
      after hypoxia. Male C3H/HeN mice received either Src inhibitor PP1 (1.5 mg/kg 
      body wt) or vehicle 1 h before hypoxia. KCs were isolated 1 h after hypoxia, 
      lysed, and immunoblotted with antibodies to Src, p38, ERK1/2, or JNK proteins. In 
      addition, KCs were cultured to measure interleukin-6 (IL-6) and monocyte 
      chemoattractant protein-1 (MCP-1) production. Hypoxia produced a significant 
      increase in KC Src and MAPK (p38, ERK, JNK) activity compared with normoxic 
      controls. This was associated with an increase in IL-6 and MCP-1 production. 
      Treatment with PP1 abolished the increase in KC Src activation as well as p38 
      activity. However, PP1 did not prevent the increase in KC ERK1/2 or JNK 
      phosphorylation. Furthermore, administration of PP1 prevented the hypoxia-induced 
      increase in IL-6 but not MCP-1 release by KC. Additional in vitro results suggest 
      that p38 but not ERK1/2 or JNK are critical for KC IL-6 production. In contrast, 
      the production of MCP-1 by KC was found to be independent of MAPK. Thus hypoxia 
      increases KC IL-6 production by p38 MAPK activation via Src-dependent pathway. 
      Src kinases may therefore be a novel therapeutic target for preventing immune 
      dysfunction following low-flow conditions in trauma patients.
FAU - Thobe, Bjorn M
AU  - Thobe BM
AD  - Center for Surgical Research, The University of Alabama at Birmingham, Volker 
      Hall G094, 1670 University Boulevard, Birmingham, AL 35294-0019, USA.
FAU - Frink, Michael
AU  - Frink M
FAU - Choudhry, Mashkoor A
AU  - Choudhry MA
FAU - Schwacha, Martin G
AU  - Schwacha MG
FAU - Bland, Kirby I
AU  - Bland KI
FAU - Chaudry, Irshad H
AU  - Chaudry IH
LA  - eng
GR  - R01 GM 37127/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20060329
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine)
RN  - 0 (AG 1879)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Cell Separation/methods
MH  - Chemokine CCL2/metabolism
MH  - Disease Models, Animal
MH  - Hypoxia/*immunology
MH  - Interleukin-6/*biosynthesis/immunology
MH  - Kupffer Cells/drug effects/*immunology
MH  - MAP Kinase Signaling System
MH  - Male
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Phosphorylation
MH  - Pyrazoles/pharmacology
MH  - Pyrimidines/pharmacology
MH  - Signal Transduction
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
MH  - src-Family Kinases/antagonists & inhibitors/*metabolism
EDAT- 2006/03/31 09:00
MHDA- 2006/09/13 09:00
CRDT- 2006/03/31 09:00
PHST- 2006/03/31 09:00 [pubmed]
PHST- 2006/09/13 09:00 [medline]
PHST- 2006/03/31 09:00 [entrez]
AID - 00076.2006 [pii]
AID - 10.1152/ajpcell.00076.2006 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2006 Sep;291(3):C476-82. doi: 
      10.1152/ajpcell.00076.2006. Epub 2006 Mar 29.