Back to Search
Start Over
Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability.
- Source :
- Nature; 12/13/2012, Vol. 492 Issue 7428, p252-255, 4p, 4 Graphs
- Publication Year :
- 2012
-
Abstract
- The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1? (IL-1?), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-?B (NF-?B)-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-?B pathway remain poorly defined. Here we show that the direct, immediate and disruptive effects of IL-1? on endothelial stability in a human in vitro cell model are NF-?B 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-1? signalling pathway distinct from that mediated by NF-?B. 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00280836
- Volume :
- 492
- Issue :
- 7428
- Database :
- Complementary Index
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 84244220
- Full Text :
- https://doi.org/10.1038/nature11603