Stimulation of FcγR receptors induces monocyte chemoattractant protein-1 in the human monocytic cell line THP-1 by a mechanism involving IκB-α degradation and formation of p50/p65 NF-κB/Rel complexes

Abstract

THP-1 monocytic/macrophage cells were stimulated via their FcγR receptors with insoluble aggregates of human IgG and the production of the C-C chemokine monocyte chemoattractant protein (MCP)-1 assayed. A dose- and time-dependent production of MCP-1 comparable to that produced by the most potent agonists could be detected in the culture medium by a sensitive ELISA assay. This was accompanied by a parallel activation of the transcription factor NF-κB as judged from both the appearance of κB-binding activity containing p50/p65 NF-κB/Rel complexes in the nuclear extract and the disappearance of the NF-κB inhibitor Iκ-B-α in the cell lysate. In contrast, IκB-β and IκB-ε expression was not modified, thus pointing to the occurrence of a selective degradation of IκB-α under those conditions. Attempts to modulate MCP-1 production with compounds that display inhibitory effects on the activation of NF-κB such as the proteasome inhibitor N-acetyl-leucinyl-leucinyl-norleucinal, the antioxidant pyrrolidine dithiocarbamate and the salicylate derivative 2-hydroxy-4-trifluoromethylbenzoic acid showed a parallel effect on both MCP-1 production and NF-κB activation, thus pointing to the involvement of κB-binding sites on the transcriptional regulation of MCP-1 production. Our findings suggest the existence in monocytic cells of a signaling mechanism initiated by cross-linking of low-affinity FcγR, most likely of the FcγRII family since THP-1 cells do not express FcγRI11 receptors, that involves activation of NF-κB associated to the proteolytic degradation of IκB-α and leads to the transcriptional upregulation of MCP-1.