Publication Date:
2012-11-13
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521847/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521847/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Weiquan -- London, Nyall R -- Gibson, Christopher C -- Davis, Chadwick T -- Tong, Zongzhong -- Sorensen, Lise K -- Shi, Dallas S -- Guo, Jinping -- Smith, Matthew C P -- Grossmann, Allie H -- Thomas, Kirk R -- Li, Dean Y -- R01 CA163970/CA/NCI NIH HHS/ -- R01 HL065648/HL/NHLBI NIH HHS/ -- R01 HL084516/HL/NHLBI NIH HHS/ -- U54 HL112311/HL/NHLBI NIH HHS/ -- England -- Nature. 2012 Dec 13;492(7428):252-5. doi: 10.1038/nature11603. Epub 2012 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Utah, Salt Lake City, Utah 84112, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23143332" target="_blank"〉PubMed〈/a〉
Keywords:
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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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