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RIP1 and Inflammation Mediated Septic Liver Injury
Author(s) -
McNeal Sam,
Chung ChunShiang,
Ayala Alfred
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.571.3
Subject(s) - fas receptor , liver injury , inflammation , apoptosis , sepsis , signal transduction , programmed cell death , fadd , kinase , immunology , western blot , medicine , tumor necrosis factor alpha , pharmacology , biology , cancer research , microbiology and biotechnology , caspase , biochemistry , gene
RIP1 is a death domain containing kinase that interacts with the death domains of Fas (CD95) and TNF. RIP1 is understood to play a role in caspase independent cell death and has been reported to increase concomitantly with increased CD95 expression in response to a variety of insults such as ischemia/reperfusion injury and in experimental stroke. Thus, it was our hypothesis that as signaling through both Fas and TNF play pathologic roles in experimental sepsis (cecal ligation & puncture, CLP), that in some fashion up regulation of RIP1 would be involved down stream signaling contributing to septic liver damage observed in this model. To assess the contribution of RIP1 to this process we attempted block its expression with RIP1 specific siRNA as well as look at concomitant alterations in its expression in the liver as well as the development of liver damage. Surprisingly, no change in septic mortality was observed when RIP1 was silenced using RIP1 siRNA vs. scrambled seq. Furthermore, while we have demonstrated increased CD95 levels on hepatocytes during sepsis, when we attempt to determine the extent of RIP1 expression in CLP (24 h post) mouse hepatocytes, the RIP1 signal (as assessed by western blot) was lost in these same cells. Subsequently, we attempted to antagonize RIP1 activity using the selective inhibitor necrostatin 1 (Nec1). Interestingly, our preliminary data indicate that when Nec1 is injected into mice subjected to CLP we observe a decline in the blood levels of pro‐inflammatory cytokines; however, an increase in Alanine aminotransferase (ALT) levels (an index of liver damage) was also seen. Together these findings suggest that signaling via RIP1 may not be a central pathway involved in mediating pathological signaling for Fas or TNF in the septic liver (supported by NIH GM53209).