Faculty Collaboration Database

Implications of proteasome inhibition: an enhanced macrophage phenotype. Cell Immunol 2004 Feb;227(2):140-7

Date

05/12/2004

Pubmed ID

15135296

DOI

10.1016/j.cellimm.2004.03.005

Scopus ID

2-s2.0-2342630414 (requires institutional sign-in at Scopus site)   31 Citations

Abstract

The objective of this study was to elucidate the role of the cellular proteasome on endotoxin-mediated activation of the macrophage. To study this role, THP-1 cells were stimulated with lipopolysaccharide (LPS) with selective cells being pretreated with the proteasome inhibitor, lactacystin or MG-132. LPS stimulation led to the phosphorylation and degradation of IRAK, followed by activation of JNK/SAPK, ERK 1/2, and p38. Subsequently, LPS induced the degradation of IkappaB, and the nuclear activation of NF-kappaB and AP-1. Activation of these pathways was associated with the production of IL-6, IL-8, IL-10, and TNF-alpha. Proteasome inhibition with either lactacystin or MG-132 attenuated LPS-induced IRAK degradation, and enhanced activation of JNK/SAPK, ERK 1/2, and p38. Proteasome inhibition, also, led to increased LPS-induced AP-1 activation, and attenuated LPS-induced IkappaB degradation resulting in abolished NF-kappaB activation. Proteasome inhibition led to significant modulation of LPS-induced cytokine production; increased IL-10, no change in IL-6, and decreased IL-8, and TNF-alpha. Thus, this study demonstrates that cellular proteasome is critical to regulation of LPS-induced signaling within the macrophage, and inhibition of the proteasome results in a conversion to an anti-inflammatory phenotype.

Author List

Cuschieri J, Gourlay D, Garcia I, Jelacic S, 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

Cell Line
Cysteine Endopeptidases
Endotoxins
Enzyme Activation
Humans
I-kappa B Kinase
Interleukin-1 Receptor-Associated Kinases
Interleukin-8
Macrophage Activation
Mitogen-Activated Protein Kinases
Multienzyme Complexes
NF-kappa B
Phenotype
Proteasome Endopeptidase Complex
Protein Kinases
Transcription Factor AP-1
Tumor Necrosis Factor-alpha