Journal
MOLECULAR IMMUNOLOGY
Volume 46, Issue 8-9, Pages 1854-1859Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2009.01.004
Keywords
Inflammation; Osteoarthritis; Rheumatoid arthritis; TNF alpha
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Funding
- German-Israel foundation (GIF) [G-374-171.02/94]
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In order to determine the mechanisms by which a chronic inflammatory network can be maintained in the arthritic joint, we examined whether fibroblast-like synoviocytes (FLS) could provide feedback signals after their stimulation by inflammatory cytokines. FLS and dermal fibroblasts (DF) were derived from rheumatoid arthritis (RA), osteoarthritis (OA) and post-trauma patients. These two cell types were then stimulated with 10 nanogram/ml of TNF alpha, IL-1 beta and IL-17 alone or in combination treatments. Specific mRNA expression of IL-23 p19 was quantitated by real-time PCR and its protein by immunoprecipitation. A striking specific synergistic induction of IL-23 p19 versus IL-12 p35 mRNA expression was noted after stimulation with IL-17 and TNF alpha in FLS, and to a lesser degree in DF (p < 0.043). This synergistic response was composed of an initial priming step by IL-17, thus making FLS hyperresponsive to TNF alpha-mediated stimulation. In contrast, IL-1 beta mediated induction of IL-23 p19 expression was cell-specific. Induction of IL-23 p19 expression by IL-1 beta was present in FLS but almost absent in the DF derived from the same patients. Furthermore, IL-1 beta did not synergize with IL-17 to induce IL-23 p19 expression. Immunoprecipitation of FLS cellular lysates after stimulation with IL-17 and TNF alpha detected p19 protein and this was enhanced by the addition of IL-1 beta. However, no co-immunoprecipitation of the p40 subunit of IL-23 was noted from the same cells. Thus, FLS are potently regulated by inflammatory cytokines to specifically express IL-23 p19. Additional byproducts of the inflammatory milieu may be required for the generation and secretion of bioactive IL-23. (C) 2009 Elsevier Ltd. All rights reserved.
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