title: Synergism between tumor necrosis factor alpha and interleukin-17 to induce IL-23 p19 expression in fibroblast-like synoviocytes.
abstract: 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 TNFalpha, IL-1beta 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 TNFalpha 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 TNFalpha-mediated stimulation. In contrast, IL-1beta mediated induction of IL-23 p19 expression was cell-specific. Induction of IL-23 p19 expression by IL-1beta was present in FLS but almost absent in the DF derived from the same patients. Furthermore, IL-1beta did not synergize with IL-17 to induce IL-23 p19 expression. Immunoprecipitation of FLS cellular lysates after stimulation with IL-17 and TNFalpha detected p19 protein and this was enhanced by the addition of IL-1beta. 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.
authors.affiliation: Allergy and Immunology Institute,Assaf-Harofeh Medical Center, Zerifin 70300, Israel. goldbergsm@yahoo.com
authors.forename: Michael
authors.initials: M
authors.lastname: Goldberg
authors.forename: Orna
authors.initials: O
authors.lastname: Nadiv
authors.forename: Noemi
authors.initials: N
authors.lastname: Luknar-Gabor
authors.forename: Gabriel
authors.initials: G
authors.lastname: Agar
authors.forename: Yiftah
authors.initials: Y
authors.lastname: Beer
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Katz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D053760:Interleukin-23 Subunit p19 / Q000235:genetics* / Q000378:metabolism; D007718:Knee Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha