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Fibroblasts from methotrexate-sensitive mice accumulate methotrexate polyglutamates but those from

Xin You1, Adrienne Williams, Thierry Dervieux

  • 1Division of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Beijing, China. xn_you@yahoo.com

Clinical and Experimental Rheumatology
|March 8, 2013
PubMed
Abstract

Insights

Methotrexate (MTX) resistance in mice is linked to reduced accumulation of MTX polyglutamates. This diminished accumulation leads to less inhibition of AICAR transformylase (ATIC) and decreased adenosine release, impacting anti-inflammatory effects.

Area of Science:

  • Pharmacology
  • Immunology
  • Biochemistry

Background:

  • Methotrexate (MTX) exerts anti-inflammatory effects by increasing adenosine release.
  • MTX resistance in certain mouse strains correlates with a lack of adenosine increase.
  • Intracellular MTX polyglutamates are known to inhibit AICAR transformylase (ATIC), promoting adenosine release.

Purpose of the Study:

  • To investigate the difference in MTX polyglutamate accumulation in MTX-resistant versus MTX-sensitive mouse cells.
  • To determine if reduced MTX polyglutamate accumulation contributes to MTX resistance.

Main Methods:

  • Dermal fibroblasts (DF) from MTX-sensitive (BALBc) and MTX-resistant (DBA/1J) mice were cultured with MTX.
  • Adenosine concentrations in cell supernatants were measured using liquid chromatography.
  • Intracellular MTX polyglutamate (MTXPG1-5) levels and ATIC activity were assessed.

Main Results:

  • MTX significantly increased adenosine production in sensitive BALBc DF but not in resistant DBA/1J DF.
  • Intracellular MTX polyglutamates were detected only in BALBc DF after MTX treatment.
  • ATIC activity was inhibited by MTX in BALBc DF, but not in DBA/1J DF.

Conclusions:

  • Diminished accumulation of MTX polyglutamates in resistant mouse cells leads to reduced ATIC inhibition.
  • This reduced ATIC inhibition results in lower adenosine accumulation, explaining resistance to MTX's anti-inflammatory effects.

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