CHEMOKINE GENE-EXPRESSION IN BONE-MARROW STROMAL CELLS - DOWN-REGULATION WITH SODIUM-SALICYLATE

Chemotactic cytokines, chemokines, have been shown to influence the pr oliferation of hematopoietic progenitor cells. Thus, regulation of che mokine production by bone marrow accessory cells is a critical aspect of stromal cell regulation of hematopoiesis. We have previously report ed that monocyte chemotactic protein-1 (MCP-1 or MCP-1/JE) and interfe ron inducible protein 10 kD (IP-10) are both induced in murine bone ma rrow 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 investiga ted 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 m RNA 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 s alicylate is slow and partial. Sodium salicylate-mediated suppression of mRNA expression is attributable neither to de novo synthesis of int ermediary protein(s) nor to the destabilization of mature mRNA transcr ipts. On the other hand, sodium salicylate downregulates the transcrip tional activity of both genes. Furthermore, IL-1 alpha induces activat ion of transcription factor nuclear factor (NF)-kB, and sodium salicyl ate suppresses it in a dose-dependent manner. We conclude that while p osttranscriptional events remain unaffected, inhibition of NF-kB activ ation by sodium salicylate may account for the suppression of chemokin e gene expression at the transcriptional level. (C) 1995 by The Americ an Society of Hematology.