PMID- 23143332
OWN - NLM
STAT- MEDLINE
DCOM- 20121221
LR  - 20220311
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 492
IP  - 7428
DP  - 2012 Dec 13
TI  - Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular 
      stability.
PG  - 252-5
LID - 10.1038/nature11603 [doi]
AB  - The innate immune response is essential for combating infectious disease. 
      Macrophages and other cells respond to infection by releasing cytokines, such as 
      interleukin-1beta (IL-1beta), which in turn activate a well-described, 
      myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-kappaB 
      (NF-kappaB)-dependent transcriptional pathway that results in inflammatory-cell 
      activation and recruitment. Endothelial cells, which usually serve as a barrier 
      to the movement of inflammatory cells out of the blood and into tissue, are also 
      critical mediators of the inflammatory response. Paradoxically, the cytokines 
      vital to a successful immune defence also have disruptive effects on endothelial 
      cell-cell interactions and can trigger degradation of barrier function and 
      dissociation of tissue architecture. The mechanism of this barrier dissolution 
      and its relationship to the canonical NF-kappaB pathway remain poorly defined. Here 
      we show that the direct, immediate and disruptive effects of IL-1beta on endothelial 
      stability in a human in vitro cell model are NF-kappaB independent and are instead 
      the result of signalling through the small GTPase ADP-ribosylation factor 6 
      (ARF6) and its activator ARF nucleotide binding site opener (ARNO; also known as 
      CYTH2). Moreover, we show that ARNO binds directly to the adaptor protein MYD88, 
      and thus propose MYD88-ARNO-ARF6 as a proximal IL-1beta signalling pathway distinct 
      from that mediated by NF-kappaB. Finally, we show that SecinH3, an inhibitor of ARF 
      guanine nucleotide-exchange factors such as ARNO, enhances vascular stability and 
      significantly improves outcomes in animal models of inflammatory arthritis and 
      acute inflammation.
FAU - Zhu, Weiquan
AU  - Zhu W
AD  - Department of Medicine, University of Utah, Salt Lake City, Utah 84112, USA.
FAU - London, Nyall R
AU  - London NR
FAU - Gibson, Christopher C
AU  - Gibson CC
FAU - Davis, Chadwick T
AU  - Davis CT
FAU - Tong, Zongzhong
AU  - Tong Z
FAU - Sorensen, Lise K
AU  - Sorensen LK
FAU - Shi, Dallas S
AU  - Shi DS
FAU - Guo, Jinping
AU  - Guo J
FAU - Smith, Matthew C P
AU  - Smith MC
FAU - Grossmann, Allie H
AU  - Grossmann AH
FAU - Thomas, Kirk R
AU  - Thomas KR
FAU - Li, Dean Y
AU  - Li DY
LA  - eng
GR  - R01 CA163970/CA/NCI NIH HHS/United States
GR  - R01 HL065648/HL/NHLBI NIH HHS/United States
GR  - R01 HL084516/HL/NHLBI NIH HHS/United States
GR  - U54 HL112311/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20121111
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (ADP-Ribosylation Factor 6)
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Cadherins)
RN  - 0 (GTPase-Activating Proteins)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (NF-kappa B)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Purines)
RN  - 0 (QS11 compound)
RN  - 0 (Receptors, Interleukin)
RN  - 0 (SC 514)
RN  - 0 (Thiophenes)
RN  - 0 (cytohesin-2)
RN  - EC 3.6.5.2 (ADP-Ribosylation Factors)
RN  - EC 3.6.5.2 (ARF6 protein, human)
SB  - IM
CIN - Nat Rev Rheumatol. 2013 Jan;9(1):2. PMID: 23183926
MH  - ADP-Ribosylation Factor 6
MH  - ADP-Ribosylation Factors/*metabolism
MH  - Adjuvants, Immunologic/pharmacology
MH  - Animals
MH  - Arthritis/pathology
MH  - Cadherins/metabolism
MH  - Capillary Permeability/drug effects
MH  - Cell Line
MH  - Endothelial Cells/drug effects
MH  - Enzyme Activation/drug effects
MH  - GTPase-Activating Proteins/*metabolism
MH  - Humans
MH  - Interleukin-1beta/pharmacology
MH  - Myeloid Differentiation Factor 88/*metabolism
MH  - NF-kappa B/metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Transport/drug effects
MH  - Purines/pharmacology
MH  - Receptors, Interleukin/*metabolism
MH  - Signal Transduction
MH  - Thiophenes/pharmacology
PMC - PMC3521847
MID - NIHMS409170
EDAT- 2012/11/13 06:00
MHDA- 2012/12/22 06:00
PMCR- 2013/06/13
CRDT- 2012/11/13 06:00
PHST- 2011/12/09 00:00 [received]
PHST- 2012/09/19 00:00 [accepted]
PHST- 2012/11/13 06:00 [entrez]
PHST- 2012/11/13 06:00 [pubmed]
PHST- 2012/12/22 06:00 [medline]
PHST- 2013/06/13 00:00 [pmc-release]
AID - nature11603 [pii]
AID - 10.1038/nature11603 [doi]
PST - ppublish
SO  - Nature. 2012 Dec 13;492(7428):252-5. doi: 10.1038/nature11603. Epub 2012 Nov 11.