Implications of proteasome inhibition: an enhanced macrophage phenotype

• Published in: Cellular immunology Vol. 227; no. 2; pp. 140 - 147
• Main Authors: Cuschieri, Joseph, Gourlay, David, Garcia, Iris, Jelacic, Sandra, Maier, Ronald V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.02.2004
• Subjects: AP-1; Cell Line; Chemokine; Cysteine Endopeptidases - physiology; Cytokine; Endotoxin; Endotoxins - pharmacology; Enzyme Activation; ERK 1/2; Humans; I-kappa B Kinase; Interleukin-1 Receptor-Associated Kinases; Interleukin-8 - biosynthesis; JNK/SAPK; Macrophage; Macrophage Activation; Mitogen-Activated Protein Kinases - metabolism; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - physiology; NF-kappa B - metabolism; NF-κB; P38; Phenotype; Proteasome; Proteasome Endopeptidase Complex; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Chemokine; NF-κB; P38; JNK/SAPK; Cytokine; ERK 1/2; Endotoxin; AP-1; Macrophage; Proteasome
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2004.03.005

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 IκB, and the nuclear activation of NF-κB and AP-1. Activation of these pathways was associated with the production of IL-6, IL-8, IL-10, and TNF-α. 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 IκB degradation resulting in abolished NF-κB 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-α. 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.