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 insolubleaggregates of human IgG and the production of the C–C chemokine monocyte chemoattractantprotein (MCP)-1 assayed. A dose- and time-dependent production of MCP-1 comparable to thatproduced by the most potent agonists could be detected in the culture medium by a sensitiveELISA assay. This was accompanied by a parallel activation of the transcription factor NF-κBasjudged from both the appearance ofκB-binding activity containing p50/p65 NF-κB/Rel complexes inthe nuclear extract and the disappearance of the NF-κB inhibitor IκB-αin the cell lysate. Incontrast, IκB-βand IκB-εexpression was not modified, thus pointing to the occurrence of aselective degradation of IκB-αunder those conditions. Attempts to modulate MCP-1 productionwith compounds that display inhibitory effects on the activation of NF-κB such as the proteasomeinhibitorN-acetyl-leucinyl-leucinyl-norleucinal, the antioxidant pyrrolidine dithiocarbamate and thesalicylate derivative 2-hydroxy-4-trifluoromethylbenzoic acid showed a parallel effect on bothMCP-1 production and NF-κB activation, thus pointing to the involvement ofκB-binding sites onthe transcriptional regulation of MCP-1 production. Our findings suggest the existence inmonocytic cells of a signaling mechanism initiated by cross-linking of low-affinity FcγR, most likelyof the FcγRII family since THP-1 cells do not express FcγRIII receptors, that involves activation ofNF-κB associated to the proteolytic degradation of IκB-αand leads to the transcriptional up-regulation of MCP-1