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

Int J Immunopharmacol. 2000 Aug;22(8):615-21. doi: 10.1016/s0192-0561(00)00024-2.

Abstract

Multiple immune system actions have been ascribed to paclitaxel (taxol), a novel anticancer drug, including the capacity to induce macrophage antitumor cytotoxic molecule production. In the present studies, we demonstrated that paclitaxel produced a selective inhibition of lipopolysaccharide (LPS)-induced B cell proliferation. Similarly, in vitro polyclonal antibody-forming cell responses also were found to be inhibited by paclitaxel. Conversely, paclitaxel exhibited no inhibitory effects on concanavalin A (Con A)-induced T cell proliferation. To study the pathway leading to paclitaxel-induced immunosuppression, we analyzed Raf-1/ERK and JNK/p38 MAPK pathways, both of which have been reported to be involved in LPS signaling. Our results indicate that taxol treatment inhibits Raf-1 kinase activation while having no effect on ERK activation suggesting that ERK activation is distinct from upstream Raf-1 kinase in taxol-induced immunomodulation. Furthermore, paclitaxel pretreatment caused down-regulation 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 LPS stimulation by pre-exposing them to paclitaxel. Taken together, these results suggest that down-regulation of JNK/p38 MAP kinase may contribute to paclitaxel-induced immunosuppression in mouse splenic lymphocytes.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cell Line
  • Female
  • Immunosuppressive Agents / pharmacology*
  • Lipopolysaccharides / pharmacology*
  • Lymphocyte Activation / drug effects*
  • Lymphocytes / drug effects
  • Lymphocytes / immunology
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Paclitaxel / pharmacology*
  • Proto-Oncogene Proteins c-raf / metabolism
  • Spleen / cytology
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Antineoplastic Agents, Phytogenic
  • Immunosuppressive Agents
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Paclitaxel