| Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability. | |
| | |
MedLine Citation:
|
PMID: 23143332 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1β (IL-1β), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-κB (NF-κB)-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-κB pathway remain poorly defined. Here we show that the direct, immediate and disruptive effects of IL-1β on endothelial stability in a human in vitro cell model are NF-κB 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-1β signalling pathway distinct from that mediated by NF-κB. 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. |
| | |
Authors:
|
Weiquan Zhu; Nyall R London; Christopher C Gibson; Chadwick T Davis; Zongzhong Tong; Lise K Sorensen; Dallas S Shi; Jinping Guo; Matthew C P Smith; Allie H Grossmann; Kirk R Thomas; Dean Y Li |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-11-11 |
Journal Detail:
|
Title: Nature Volume: 492 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2012 Dec |
Date Detail:
|
Created Date: 2012-12-13 Completed Date: 2012-12-21 Revised Date: 2013-05-14 |
Medline Journal Info:
|
Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
|
Languages: eng Pagination: 252-5 Citation Subset: IM |
Affiliation:
|
Department of Medicine, University of Utah, Salt Lake City, Utah 84112, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
ADP-Ribosylation Factors
/
metabolism* Adjuvants, Immunologic / pharmacology Animals Arthritis / pathology Cadherins / metabolism Capillary Permeability / drug effects Cell Line Endothelial Cells / drug effects Enzyme Activation / drug effects GTPase-Activating Proteins / metabolism* Humans Interleukin-1beta / pharmacology Myeloid Differentiation Factor 88 / metabolism* NF-kappa B / metabolism Protein Kinase Inhibitors / pharmacology Protein Transport / drug effects Purines / pharmacology Receptors, Interleukin / metabolism* Signal Transduction Thiophenes / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
|
R01 CA163970/CA/NCI NIH HHS; R01 HL065648/HL/NHLBI NIH HHS; U54 HL112311/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Adjuvants, Immunologic; 0/Cadherins; 0/GTPase-Activating Proteins; 0/Interleukin-1beta; 0/Myeloid Differentiation Factor 88; 0/NF-kappa B; 0/Protein Kinase Inhibitors; 0/Purines; 0/QS11 compound; 0/Receptors, Interleukin; 0/SC 514; 0/Thiophenes; 0/cytohesin-2; EC 3.6.5.2/ADP-Ribosylation Factors; EC 3.6.5.2/ADP-ribosylation factor 6 |
| Comments/Corrections | |
Comment In:
|
Nat Rev Rheumatol. 2013 Jan;9(1):2
[PMID:
23183926
]
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Use of high flow nasal cannula in critically ill infants, children, and adults: a critical review of...
Next Document: The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca(2+) and cAMP.