Chemokine gene expression in bone marrow stromal cells: downregulation with sodium salicylate.

ABSTRACT

Chemotactic cytokines, chemokines, have been shown to influence the proliferation of hematopoietic progenitor cells. Thus, regulation of chemokine production by bone marrow accessory cells is a critical aspect of stromal cell regulation of hematopoiesis. We have previously reported that monocyte chemotactic protein-1 (MCP-1 or MCP-1/JE) and interferon inducible protein 10 kD (IP-10) are both induced in murine bone marrow stromal cells +/(+)-1.LDA11 after stimulation with the inflammatory agents interleukin-1 alpha (IL-1 alpha), interferon-gamma (IFN-gamma), or lipopolysaccharide (LPS). In the present study, we have investigated the effect of sodium salicylate, an antiinflammatory agent, on the IL-1 alpha-induced expression of MCP-1/JE and IP-10 genes in stromal cells. Sodium salicylate attenuates the levels of MCP-1/JE and IP-10 mRNA in a concentration- and time-dependent manner. The suppression of MCP-1/JE mRNA is reversible, whereas IP-10 mRNA expression is more or less irreversibly affected as its recovery from the effect of sodium salicylate is slow and partial. Sodium salicylate-mediated suppression of mRNA expression is attributable neither to de novo synthesis of intermediary protein(s) nor to the destabilization of mature mRNA transcripts. On the other hand, sodium salicylate downregulates the transcriptional activity of both genes. Furthermore, IL-1 alpha induces activation of transcription factor nuclear factor (NF)-kB, and sodium salicylate suppresses it in a dose-dependent manner. We conclude that while posttranscriptional events remain unaffected, inhibition of NF-kB activation by sodium salicylate may account for the suppression of chemokine gene expression at the transcriptional level.