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-alpha (GRalpha) 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 GRalpha, 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 GRalpha, c-fos, or c-jun mRNA expression determined by RT-PCR was observed. Additionally, there were significant correlations between the amount of GRalpha 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 GRalpha 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.
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-alpha (GRalpha) 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 GRalpha, 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 GRalpha, c-fos, or c-jun mRNA expression determined by RT-PCR was observed. Additionally, there were significant correlations between the amount of GRalpha 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 GRalpha 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.
Authors: Willmar D Patino; Omar Y Mian; Ju-Gyeong Kang; Satoaki Matoba; Linda D Bartlett; Brenda Holbrook; Hugh H Trout; Louis Kozloff; Paul M Hwang Journal: Proc Natl Acad Sci U S A Date: 2005-02-22 Impact factor: 11.205