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Macrophage-derived cytokines and chemokines are involved at multiple steps of immune and inflammatory responses, and the transcriptional factor NF-κB appears to play a pivotal role in their coordinated upregulation. The anti-inflammatory agents salicylates have been proposed to act in part by inhibiting NF-κB. We have therefore studied the effects of sodium salicylate on lipopolysaccharide (LPS)-induced κB-binding activity and on cytokine and chemokine gene expression in the RAW264.7 murine macrophage cell line and compared them to those of an established NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC). PDTC (100 μM) completely abrogated LPS-induced κB-binding activity and also profoundly inhibited the induction of interleukin 1α (IL-1α), IL-1β, IL-6, IL-10, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and MCP-1 and, to a lesser extent, leukemia inhibitory factor, RANTES, and IL-1Ra. In contrast, sodium salicylate (15 to 20 mM) had no effect on NF-κB activation but, nevertheless, suppressed several LPS-induced cytokine and chemokine genes to a degree similar to that obtained with PDTC. However, compared to PDTC, sodium salicylate caused significantly less inhibition of IL-1Ra and IL-10 gene expression after LPS stimulation. Neither LPS-induced MIP-1α, MIP-1β, nor MIP-2 was significantly affected by PDTC or sodium salicylate, demonstrating that NF-κB is dispensable for the transcriptional regulation of these genes by LPS. In summary, these results suggest that both NF-κB-dependent and NF-κB-independent pathways are necessary for the induction by LPS of a complex cytokine and chemokine response. In the RAW264.7 macrophage cell line, suprapharmacological concentrations of sodium salicylate exert a potent inhibitory effect on LPS-induced cytokine gene induction but appear to accomplish this by interfering with NF-κB-independent pathways of activation.

Inhibition of Cytokine Gene Expression by Sodium Salicylate in a Macrophage Cell Line through an NF-κB-Independent Mechanism