• Eriko Takahashi, Kenji Onda, Toshihiko Hirano, Kitaro Oka, Noritaka Maruoka, Miyako Tsuyuguchi, Yasuhiro Matsumura, Tomoyuki Niitsuma, and Tohru Hayashi.
• Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Science, Japan.
• Int. Immunopharmacol. 2002 Sep 1; 2 (10): 1419-27.

AbstractResolution of the molecular mechanism(s) underlying glucocorticoid (GC) resistance is an important clinical problem when performing individualized GC therapy according to the GC response of peripheral cells in asthma. In order to investigate the mechanism(s) underlying the individual differences of lymphocyte GC response, we examined the relationship between lymphocyte sensitivity to GC in vitro and the expression of mRNAs for GC receptor (GR) alpha, GRbeta, c-fos and c-jun, which are reported to be implicated in the regulation of the pharmacological effects of GCs in asthma patients. Twenty-seven patients with bronchial asthma and 14 healthy subjects were included in the study. IC50s of prednisolone and methylprednisolone on blastogenesis of peripheral blood mononuclear cells (PBMCs) stimulated with concanavalin A in vitro were estimated. Transcripts for GRalpha, c-fos, c-jun and beta-actin genes in PBMCs were quantitatively determined by reverse transcription-competitive polymerase chain reaction (RT-cPCR) procedures. GRbeta mRNA expression was examined with an RT-PCR technique. A statistically significant positive correlation was observed between the IC50s for prednisolone (p <0.002) or methylprednisolone (p <0.001) and expression of c-fos mRNA in PBMCs of asthma patients (n = 27). Thus, the increased expression of c-fos mRNA correlated with the decreased responses of PBMCs to prednisolone and methylprednisolone in vitro. In contrast, the expression of GRalpha and c-jun mRNAs did not correlate with the IC50 for prednisolone and methylprednisolone in asthma patients. In addition, no statistically significant difference in IC50s of GCs between asthma patients with PBMCs exhibiting GRbeta mRNA and those without GRbeta mRNA expression was observed. The increased expression of c-fos mRNA suggests to attenuate PBMC response to GCs, which may contribute to progression of GC resistance in asthma. On the other hand, c-jun and GC receptor mRNA expression appears to have less influence on poor GC-response establishment.

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