Paclitaxel causes mouse splenic lymphocytes to a state hyporesponsive to lipopolysaccharide stimulation

Multiple immune system actions have been ascribed to paclitaxel (taxol), a novel anticancer drug, including the capacity to induce macrophage antitumo r cytotoxic molecule production. In the present studies, we demonstrated th at paclitaxel produced a selective inhibition of lipopolysaccharide (LPS)-i nduced B cell proliferation. Similarly, in vitro polyclonal antibody-formin g cell responses also were found to be inhibited by paclitaxel. Conversely, paclitaxel exhibited no inhibitory effects on concanavalin A (Con A)-induc ed T cell proliferation. To study the pathway leading to paclitaxel-induced immunosuppression, we analyzed Raf-1/ERK and JNK/p38 MAPK pathways, both o f which have been reported to be involved in LPS signaling. Our results ind icate that taxol treatment inhibits Raf-1 kinase activation while having no effect on ERK activation suggesting that ERK activation is distinct from u pstream Raf-1 kinase in taxol-induced immunomodulation. Furthermore, paclit axel pretreatment caused downregulation of stress-activated MAPKs, JNK and p38 MAPK in lipopolysaccharide (LPS)-stimulated mouse splenic lymphocytes, demonstrating that spleen cells are induced to a state hyporesponsive to LP S stimulation by preexposing them to paclitaxel. Taken together, these resu lts suggest that down-regulation of JNK/p38 MAP kinase may contribute to pa clitaxel-induced immunosuppression in mouse splenic lymphocytes. (C) 2000 I nternational Society for Immunopharmacology. Published by Elsevier Science Ltd. All rights reserved.