Combination of the pro-inflammatory cytokines IL-1, TNF-alpha and IL-17 leads to enhanced expression and additional recruitment of AP-1 family members, Egr-1 and NF-kappaB in osteoblast-like cells.
To determine the contribution of IL-1, TNF-alpha and IL-17 on AP-1, NF-kappaB and Egr-1 activation in cytokine induced bone destruction as observed in rheumatoid arthritis, we investigated the effect of these pro-inflammatory cytokines used alone or in combination on transcription factor activation in osteoblast-like ROS 17/2.8 cells. The effects of each cytokine were measured by RT-PCR and immunocytochemistry. IL-1 and TNF-alpha induced most of these transcription factors while IL-17 had a weak effect. IL-1 and TNF-alpha induced egr-1 and all AP-1 member expression, except fosB and junD. These two cytokines used alone induced their nuclear translocation in 30 min, except for FosB and JunB. IL-17 enhanced fra-2 and egr-1 mRNA expression, while nuclear localization was observed for Fra-1, JunD and NF-kappaB. More importantly, combination of low concentrations of these cytokines, with no effect separately, showed a synergistic effect on transcription and nuclear translocation of AP-1 members, Egr-1 and NF-kappaB. Moreover, cytokine combinations were associated with an enhanced recruitment of factors not expressed when cytokines were used alone. In conclusion, AP-1, Egr-1 and NF-kappaB pathways in osteoblast cells are very sensitive to the combined effect of pro-inflammatory cytokines through synergistic mechanisms.
Granet
Corinne
C
INSERM U 403 and Clinical Immunology Unit, Departments of Immunology and Rheumatology, Hospital E. Herriot, 5 place d'Arsonval, 69437 Lyon Cedex 03, France.
Miossec
Pierre
P
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D020381:Interleukin-17; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases