Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance

Oncogene. 2004 Apr 29;23(20):3530-40. doi: 10.1038/sj.onc.1207336.


We have recently reported that Rituximab (anti-CD20) sensitizes drug-resistant 2F7 and 10C9 B Non-Hodgkin's lymphoma (NHL) cell lines to the apoptotic effects of various chemotherapeutic drugs by downregulation of IL-10 and Bcl-2 expression. The mechanism by which Rituximab induces downregulation of IL-10 was examined. We hypothesized that Rituximab may inhibit p38 MAPK activity that regulates IL-10 expression via Sp1. Treatment of 2F7 cells with Rituximab or the p38 inhibitor SB203580 inhibited the constitutive p38 MAPK activity and resulted in the inhibition of Sp1, IL-10, STAT3, and Bcl-2. Inhibition of the Src-family PTKs, Lyn, and Src-family PTKs upstream signaling molecules of the p38MAPK pathway, by PP2, a specific Src-family kinase inhibitor, resulted in the inhibition of p38MAPK and IL-10 expression. In addition to p38 MAPK, Rituximab also inhibited NF-kappaB activity. Inhibition of the Src PTKs, MAPK, and NF-kappaB activities by Rituximab or by specific chemical inhibitors sensitized the cells to CDDP-mediated apoptosis. The above signaling-mediated effects by Rituximab were observed with similar kinetics beginning at 1 h following treatment. Thus, altogether, these results demonstrate that signaling by Rituximab results in the inhibition of the p38MAPK pathway, which in turn inhibits the transcription of IL-10 via Sp1. Inhibition of the IL-10 autocrine/paracrine loop results in the inhibition of STAT3 activity and, consequently, inhibition of Bcl-2 expression and sensitization to drugs-apoptosis. Further, Rituximab-mediated signaling identifies several new intracellular targets in NHL that may be of potential therapeutic interest for the development of new drugs in the treatment of drug-refractory NHL tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Murine-Derived
  • Antineoplastic Agents / pharmacology*
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / genetics*
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / physiology
  • NF-kappa B / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rituximab
  • STAT3 Transcription Factor
  • Signal Transduction / physiology
  • Trans-Activators / metabolism
  • p38 Mitogen-Activated Protein Kinases


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Interleukin-10
  • Rituximab
  • DNA
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases