Effect of interleukin-6 neutralization on CYP3A11 and metallothionein-1/2 expressions in arthritic mouse liver

Eur J Pharmacol. 2007 Mar 8;558(1-3):199-207. doi: 10.1016/j.ejphar.2006.11.072. Epub 2006 Dec 12.

Abstract

Rheumatoid arthritis is characterized by chronic inflammation of the synovial tissue. We examined the effect of interleukin (IL)-6 neutralization on the expression of cytochrome P450 or metallothionein-1/2 (metallothionein) during chronic phase inflammatory disease using rheumatoid arthritis model mice, human T-cell leukemia virus type I (HTLV-I) transgenic mice. Serum IL-6 concentrations of arthritis-developed HTLV-I transgenic mice were 129.9+/-26.1 pg/ml. Moreover, signal transducer and activator of transcription (STAT) 1/3 phosphorylations was observed in arthritic HTLV-I transgenic mouse livers. CYP3A11 mRNA was more strongly reduced by the development of arthritis in HTLV-I transgenic mouse livers as compared with CYP2C29 or CYP2E1 mRNAs. CYP3A protein and testosterone 6beta-hydroxylation activity also changed in a similar manner to the corresponding CYP3A11 mRNA level. On the other hand, metallothionein mRNA was significantly induced as compared with that of wild-type or non-arthritic mice. CYP3A suppression and metallothionein mRNA overexpression activity seen in the developed arthritic mice returned to the gene conditions of the non-arthritic HTLV-I transgenic mice by IL-6 antibody at 48 h after treatment. The present study has revealed that CYP3A11 and metallothionein expressions are affected by the release of IL-6 by arthritis and its systemic circulation, and neutralization of IL-6 recovered from the down-regulation of CYP3A11 mRNA and the induction of metallothionein mRNA in arthritic HTLV-I transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / metabolism*
  • Cytochrome P-450 CYP3A / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Human T-lymphotropic virus 1 / pathogenicity
  • Interleukin-6 / physiology*
  • Liver / metabolism*
  • Membrane Proteins / genetics*
  • Metallothionein / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Phosphorylation
  • RNA, Messenger / analysis
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Steroid Hydroxylases / metabolism

Substances

  • Interleukin-6
  • Membrane Proteins
  • Mt2 protein, mouse
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Cytochrome P-450 Enzyme System
  • Metallothionein
  • Steroid Hydroxylases
  • Cyp3a11 protein, mouse
  • Cytochrome P-450 CYP3A
  • steroid hormone 6-beta-hydroxylase