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

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.

• Authors: Takashi Ashino, Yoshiko Arima, Seiji Shioda, Yoichiro Iwakura, Satoshi Numazawa, Takemi Yoshida
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 558 Issue 1-3 Pg. 199-207 (Mar 08 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17239366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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)