PMID- 22424098
OWN - NLM
STAT- MEDLINE
DCOM- 20120508
LR  - 20211203
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 419
IP  - 3
DP  - 2012 Mar 16
TI  - PI3K/Akt contributes to increased expression of Toll-like receptor 4 in 
      macrophages exposed to hypoxic stress.
PG  - 466-71
LID - 10.1016/j.bbrc.2012.02.015 [doi]
AB  - Toll-like receptors (TLRs) play critical roles in triggering immune and 
      inflammatory responses by detecting invading microbial pathogens and endogenous 
      danger signals. Increased expression of TLR4 is implicated in aggravated 
      inflammatory symptoms in ischemic tissue injury and chronic diseases. Results 
      from our previous study showed that TLR4 expression was upregulated by hypoxic 
      stress mediated by hypoxia-inducible factor-1 (HIF-1) at a transcriptional level 
      in macrophages. In this study, we further investigated the upstream signaling 
      pathway that contributed to the increase of TLR4 expression by hypoxic stress. 
      Either treatment with pharmacological inhibitors of PI3K and Akt or knockdown of 
      Akt expression by siRNA blocked the increase of TLR4 mRNA and protein levels in 
      macrophages exposed to hypoxia and CoCl(2). Phosphorylation of Akt by hypoxic 
      stress preceded nuclear accumulation of HIF-1alpha. A PI3K inhibitor (LY294002) 
      attenuated CoCl(2)-induced nuclear accumulation and transcriptional activation of 
      HIF-1alpha. In addition, HIF-1alpha-mediated upregulation of TLR4 expression was blocked 
      by LY294002. Furthermore, sulforaphane suppressed hypoxia- and CoCl(2)-induced 
      upregulation of TLR4 mRNA and protein by inhibiting PI3K/Akt activation and the 
      subsequent nuclear accumulation and transcriptional activation of HIF-1alpha. 
      However, p38 was not involved in HIF-1alpha activation and TLR4 expression induced by 
      hypoxic stress in macrophages. Collectively, our results demonstrate that 
      PI3K/Akt contributes to hypoxic stress-induced TLR4 expression at least partly 
      through the regulation of HIF-1 activation. These reveal a novel mechanism for 
      regulation of TLR4 expression upon hypoxic stress and provide a therapeutic 
      target for chronic diseases related to hypoxic stress.
CI  - Copyright A(c) 2012 Elsevier Inc. All rights reserved.
FAU - Kim, So Young
AU  - Kim SY
AD  - School of Life Sciences, Gwangju Institute of Science and Technology, Republic of 
      Korea.
FAU - Jeong, Eunshil
AU  - Jeong E
FAU - Joung, Sun Myung
AU  - Joung SM
FAU - Lee, Joo Young
AU  - Lee JY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Chromones)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Isothiocyanates)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sulfoxides)
RN  - 0 (Thiocyanates)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 3G0H8C9362 (Cobalt)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EVS87XF13W (cobaltous chloride)
RN  - GA49J4310U (sulforaphane)
SB  - IM
MH  - Animals
MH  - Cell Hypoxia
MH  - Cell Line
MH  - Chromones/pharmacology
MH  - Cobalt/pharmacology
MH  - Gene Knockdown Techniques
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
MH  - Isothiocyanates
MH  - Macrophages/metabolism/physiology
MH  - Mice
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/*metabolism
MH  - RNA, Messenger/biosynthesis
MH  - *Stress, Physiological
MH  - Sulfoxides
MH  - Thiocyanates/pharmacology
MH  - Toll-Like Receptor 4/*biosynthesis
MH  - Transcription, Genetic
MH  - Up-Regulation
EDAT- 2012/03/20 06:00
MHDA- 2012/05/09 06:00
CRDT- 2012/03/20 06:00
PHST- 2012/01/27 00:00 [received]
PHST- 2012/02/03 00:00 [accepted]
PHST- 2012/03/20 06:00 [entrez]
PHST- 2012/03/20 06:00 [pubmed]
PHST- 2012/05/09 06:00 [medline]
AID - S0006-291X(12)00233-1 [pii]
AID - 10.1016/j.bbrc.2012.02.015 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2012 Mar 16;419(3):466-71. doi: 
      10.1016/j.bbrc.2012.02.015.