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

THP-1 monocytic/macrophage cells were stimulated via their Fc gamma R 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-kappa B as judged from both the appearance of Ice-binding activity containing p50/p65 NF-kappa B/Rel complexes in the nuclear extract and the disappearance of the NF-kappa B inhibitor I kappa B-alpha in the cell lysate, In contrast, I kappa B-beta and I kappa B-epsilon expression was not modified, thus pointing to the occurrence of a selective degradation of I kappa B-alpha under those conditions. Attempts to modulate MCP-1 production with compounds that display inhibitory effects on the activation of NF-kappa B 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-kappa B activation, thus pointing to the involvement of kappa B-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 Fc gamma R, most likely of the Fc gamma RII family since THP-1 cells do not express Fc gamma RIII receptors, that involves activation of NF-kappa B associated to the proteolytic degradation of I kappa B-alpha and leads to the transcriptional upregulation of MCP-1.