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Logo of arthrestherBioMed Centralbiomed central web sitesearchsubmit a manuscriptregisterthis articleArthritis Research & Therapy
 
Arthritis Res Ther. 2004; 6(3): R190–R198.
Published online Feb 26, 2004. doi:  10.1186/ar1159
PMCID: PMC416439
Increased AP-1 and NF-κB activation and recruitment with the combination of the proinflammatory cytokines IL-1β, tumor necrosis factor alpha and IL-17 in rheumatoid synoviocytes
Corinne Granet,1 Wova Maslinski,2 and Pierre Miosseccorresponding author1
1Department of Immunology and Rheumatology, INSERM U403, Hôpital E Herriot, Lyon, France
2Department of Pathophysiology and Immunology, Institute of Rheumatology, Warsaw, Poland
corresponding authorCorresponding author.
Pierre Miossec: miossec/at/univ-lyon1.fr
Received November 24, 2003; Revisions requested December 15, 2003; Revised January 27, 2004; Accepted February 12, 2004.
Abstract
To determine the contribution of IL-1β, tumor necrosis factor alpha (TNF-α) and IL-17 to AP-1, NF-κB and Egr-1 activation in rheumatoid arthritis, the effect of the cytokines used alone or in combination was measured on TF expression in rheumatoid synoviocytes. Effects on mRNA expression were measured by RT-PCR and effects on nuclear translocation were measured by immunocytochemistry. To assess the functional consequences of cytokine induction, osteoprotegerin levels were measured in synoviocyte supernatants.
IL-1β and TNF-α alone at optimal concentration (100 pg/ml) induced the nuclear translocation of NF-κB and almost all AP-1 members, except JunB and Egr-1 for IL-1β and except Fra-2 and Egr-1 for TNF-α. IL-17 was clearly less potent since no nuclear translocation was observed, except for a weak activation of Fra-1 and NF-κB. More importantly, when these cytokines were used at low concentrations, their combination showed a synergistic effect on almost all the TFs, except for Egr-1, with a particular effect on Fra-1 and NF-κB. Increased recruitment of additional factors was induced when the three cytokines were combined. IL-1 and TNF-α induced mRNA expression of c-jun while IL-17 had no effect. A synergistic effect was seen with their combination. A similar synergistic effect was observed for osteoprotegerin production when these three cytokines were combined at low concentrations.
AP-1 and NF-κB pathways were highly sensitive to the combination through synergistic mechanisms. These effects observed in rheumatoid arthritis synoviocytes may reflect the conditions found in the rheumatoid arthritis joint and may contribute to the mode of action of cytokine inhibitors.
Keywords: proinflammatory cytokines, rheumatoid arthritis, synoviocytes, transcription factors
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