Faculty Collaboration Database

Modulation of macrophage responsiveness to lipopolysaccharide by IRAK-1 manipulation. Shock 2004 Feb;21(2):182-8

Date

01/31/2004

Pubmed ID

14752294

DOI

10.1097/01.shk.0000111828.07309.26

Scopus ID

2-s2.0-4644275127 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

Local activation of the macrophage by endotoxin is essential for the eradication of invasive gram-negative infections. Circulating endotoxin at lower concentrations results in immune cell activation at distant sites leading to tissue injury. Although the cellular mechanisms involved in these potentially dissimilar events are incomplete, it appears that the proximal kinase IRAK-1 plays a role. Thus, sense and antisense IRAK-1 oligonucleotides were used to determine the role IRAK-1 plays in macrophage activation by systemic (1-100 ng/mL) and local (1000 ng/mL) concentration of lipopolysaccharide (LPS) within THP-1 cells. Within the sense group, 1-1000 ng/mL of LPS within the sense group resulted in cellular activation of ERK-1/2, p38, and JNK/SAPK and the nuclear activation of NF-kappaB and AP-1. This activation was associated with proinflammatory cytokine production and cellular spreading. Systemic concentrations of LPS within the antisense group were associated with significant attenuation of intracellular signaling, cytokine production, and cellular spreading compared with the sense group. Local concentrations of LPS within the antisense group, however, were associated only with a delay in intracellular signaling, with no effect on cytokine production or cell spreading compared with the sense group. Based on these results, it appears that IRAK-1 is essential to macrophage activation at systemic, but not local, concentrations of LPS. These data suggest that redundant pathways exist that are functional at higher concentrations of LPS. Therefore, IRAK-1 appears to be the central kinase involved in the activation of the macrophage at distant sites during septic shock but is not necessary for activation in areas of local infection.

Author List

Cuschieri J, Bulmus V, Gourlay D, Garcia I, Hoffman A, Stayton P, Maier RV

Author

David M. Gourlay MD Chief, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Blotting, Western
Cell Line
Cell Nucleus
Cell Survival
Cytokines
Dose-Response Relationship, Drug
Endotoxins
Enzyme Activation
Escherichia coli
Genetic Vectors
Humans
Inflammation
Interleukin-1 Receptor-Associated Kinases
Lipopolysaccharides
Macrophages
Membrane Glycoproteins
Oligonucleotides
Oligonucleotides, Antisense
Protein Kinases
Receptors, Cell Surface
Sepsis
Shock
Signal Transduction
Time Factors
Toll-Like Receptors