Linked Life Data

21372190

Source:http://linkedlifedata.com/resource/pubmed/id/21372190

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2011-8-2
pubmed:abstractText
Dysregulated Ca(2+) handling is prevalent during sepsis and postulated to perpetuate the aberrant inflammation underlying subsequent organ dysfunction and death. The signal transduction cascades mediating these processes are unknown. Here, we identify that CaMKI? mediates the M? response to LPS in vitro and the inflammation and organ dysfunction of sepsis in vivo. We show that LPS induced active pThr(177)-CaMKI? in RAW 264.7 cells and murine peritoneal M?, which if inhibited biochemically with STO609 (CaMKK inhibitor) or by RNAi, reduces LPS-induced production of IL-10. Transfection of constitutively active CaMKI? (CaMKI293), but not a kinase-deficient mutant (CaMKI293(K49A)), induces IL-10 release. This production of IL-10 is mediated by CaMKI?-dependent regulation of p38 MAPK activation. CaMKI? activity also mediates the cellular release of HMGB1 by colocalizing with and regulating the packaging of HMGB1 into secretory lysosomes. During endotoxemia, mice receiving in vivo CaMKI?(RNAi) display reduced systemic concentrations of IL-10 and HMGB1 in comparison with mice receiving NT(RNAi). These data support the biological relevance of CaMKI?-dependent IL-10 production and HMGB1 secretion. In a CLP model of sepsis, CaMKI?(RNAi) mice display reduced systemic concentrations of IL-10, IL-6, TNF-?, and HMGB1 in comparison with NT(RNAi) mice, which correlate with reductions in the development of renal dysfunction. These data support that CaMKI? signaling is integral to the M? responding to LPS and may also be operant in vivo in regulating the inflammation and organ dysfunction consequent to sepsis.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1938-3673
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
90
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
249-61
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Calcium/calmodulin-dependent protein kinase (CaMK) Ialpha mediates the macrophage inflammatory response to sepsis.
pubmed:affiliation
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural