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Role of mRNA Expression of Transcription Factors in Glucocorticoid Sensitivity of Peripheral Blood Mononuclear Cells and Disease State in Rheumatoid Arthritis
KENJI ONDA, EMIKO RIMBARA, TOSHIHIKO HIRANO, KITARO OKA, HARUO ABE, KOICHIRO TAHARA, HIROFUMI TAKANASHI, NORIOKI TSUBOI, TOMOYUKI NIITSUMA, and TOHRU HAYASHI
ABSTRACT. Objective. To investigate the mechanisms underlying glucocorticoid (GC) resistance in rheumatoid arthritis (RA), we evaluated the suppressive effects of prednisolone (PSL) or methylprednisolone (MPSL) on the blastogenesis of peripheral blood mononuclear cells (PBMC). We also measured the expression of mRNA for transcription factors [GC receptor-α (GRα) and activator protein-1] known to be involved in the exertion of GC effects. Methods. Twenty-six patients with RA and 17 healthy subjects were studied. IC50 of PSL and MPSL on the blastogenesis of PBMC stimulated with concanavalin A in vitro was estimated. Transcripts for GRα, c-fos, c-jun, and GAPDH genes in PBMC were quantitatively determined by real-time RT-PCR procedures. Results. The amount of c-fos transcript in PBMC from RA patients was significantly high compared to the healthy subjects (p = 0.001). However, no difference was found in the amounts of mRNA of other transcription factors between the patients and healthy subjects. When PSL or MPSL IC50 in patients were directly correlated with patients' characteristics in RA, the duration of disease showed a significant positive correlation with PSL IC50 (p = 0.035). However, no significant association of PSL or MPSL IC50 with GRα, c-fos, or c-jun mRNA expression determined by RT-PCR was observed. Additionally, there were significant correlations between the amount of GRα mRNA and inflammatory indices such as erythrocyte sedimentation rate (p < 0.001) and C-reactive protein (p < 0.05) in the RA patients. Conclusion. Chronic exposure to inflammation in RA suggests a decrease in the GC sensitivity of peripheral lymphocytes. Although c-fos and GRα transcripts in PBMC have been implicated in the pathology of RA, the amount of expression of these factors may not be critical for the development of GC insensitivity in the PBMC in RA. (J Rheumatol 2004;31:464-9) Key Indexing Terms:
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From the Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Science; and the 3rd Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan. Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education Culture, Sports, Science and Technology, Japan (Grant no. 09672337). K. Onda, BS; E. Rimbara, BS; T. Hirano, PhD; K. Oka, PhD, Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Science; H. Abe, MD, PhD; K. Tahara, MD, PhD; H. Takanashi, MD, PhD; N. Tsuboi, MD, PhD; T. Niitsuma, MD, PhD; T. Hayashi, MD, PhD, 3rd Department of Internal Medicine, Tokyo Medical University. Address reprint requests to Dr. K. Onda, Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail:knjond@ps.toyaku.ac.jp Submitted January 9, 2003; revision accepted October 6, 2003. |