A novel function of phosphorothioate oligodeoxynucleotides as chemoattractants for primary macrophages

Phosphorothioate cytosine-guanine oligodeoxynucleotides (CpG PS-ODNs) has b een reported to induce Th1 immune responses against coadministered Ags more efficiently than phosphodiester CpG ODNs (CpG PO-ODNs). Here, we demonstra ted that PS-ODNs, but not PO-ODNs, have a chemotactic effect on primary mac rophages, which is independent of the CpG motif. In addition, the conjugati on of a hexameric dG run (dG(6) run) at the 3' terminus reduced the concent ration required for the optimal chemotactic activity of PS-ODNs by similar to 10-fold. Endosomal maturation blockers, such as monensin and chloroquine , inhibited the chemotactic effect of PS-ODNs. The inhibition of the activi ties of p38 mitogen-activated protein (MAP) kinase, and extracellular signa l-related kinases (ERKs) as well as phosphoinositide 3-kinase with their sp ecific inhibitors also resulted in suppressing the chemotaxis of primary ma crophages induced by PS-ODNs. These results indicate that the PS-ODN-mediat ed chemotaxis requires the activation of ERKs, p38 MAP kinase, and phosphoi nositide 3-kinase as well as endosomal maturation. In addition, the phospho rylations of the p38 MAP kinase, ERKs, and protein kinase B, Akt, were indu ced by PS-ODN, which were further enhanced by the presence of both a dG(6) run and CpG motifs. Our findings suggest that the chemotactic activity of P S-ODNs may be one of the mechanisms by which PS-ODNs exhibit stronger immun omodulatory activities than PO-ODNs in vivo.