Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24604832
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Tyrosine kinase 2 promotes sepsis-associated lethality by facilitating production
of interleukin-27
#MMPMID24604832
Bosmann M
; Strobl B
; Kichler N
; Rigler D
; Grailer JJ
; Pache F
; Murray PJ
; Müller M
; Ward PA
J Leukoc Biol
2014[Jul]; 96
(1
): 123-31
PMID24604832
show ga
The aim of this study was to test the hypothesis that gene expression and release
of IL-27 may be modulated by Tyk2. Macrophages derived from the peritoneum or
bone marrow of C57BL/10SnJ (WT) mice produced abundant amounts of IL-27(p28)
following TLR4 activation by LPS. In contrast, production of IL-27(p28), but not
EBI3, was reduced by ?50% in TLR4-activated macrophages derived from mice with
genetic deficiency of Tyk2 compared with WT macrophages. Frequencies of
IL-27(p28)+F4/80+CD11b+ cells were lower in TLR4-activated macrophages derived
from Tyk2-/- mice. Mechanistically, Tyk2-/- resulted in disruption of a type I
IFN-dependent mechanism for production of IL-27(p28), which was induced by type I
IFNs, and release of IL-27 was defective in macrophages from IFN-?-/- and
IFNAR1-/- mice. In contrast, Tyk2 was not required to mediate the effects of
IL-27 on target gene expression in CD4(+) T cells. In vivo, we observed that
Tyk2-/- mice have improved survival following endotoxic shock or polymicrobial
sepsis induced by CLP. Plasma levels of IL-27(p28) during endotoxic shock or
polymicrobial sepsis were markedly reduced in Tyk2-/- mice compared with WT mice.
Disruption of IL-27 signaling using IL-27RA-/- mice was protective against
sepsis-associated mortality. These data suggest that Tyk2 may mediate adverse
outcomes of SIRS by promoting the production of IL-27. In conclusion, this report
identifies Tyk2 as a prerequisite factor in the molecular networks that are
involved in generation of IL-27.
free
free
free
