Interleukin-4 inhibits RANKL-induced expression of NFATc1 and c-Fos: A possible mechanism for downregulation of osteoclastogenesis

Complex Regulation of Tartrate-resistant Acid Phosphatase (TRAP) Expression by Interleukin 4 (IL-4)

“…Several mechanisms have been proposed for these effects: antagonism of the RANKL-activated NF-B and mitogen-activate protein kinase pathways (30,31,34,43), down-regulation of NFATc1 and c-Fos expression in progenitor cells (32), regulation of Ca 2ϩ signaling (31), regulation of PPAR␥1 (33), and suppression of RANK expression (29). We previously reported that the inhibitory effects of IL-4 on the bone resorbing activity of osteoclasts are STAT6-dependent (29).…”

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

“…IL-17 is a potent inducer of RANK and strongly induces osteoclastogenesis. In contrast, it has been reported that IL-4 (in part) inhibits osteoclast generation through the downregulation of RANK, involving signaling through c-Fos and NF-ATc1 (24,50). Interferon-␥, on the other hand, interferes with the signaling of RANKL by reducing TRAF6 expression in a selective manner.…”

“…The TRAF-binding domains of RANK are important for the RANK-dependent induction of NF-B and JNK (21,23). In addition, the signaling pathways via the transcription factors c-Fos and nuclear factor of activated T cells c1 (NF-ATc1) seem to be important for RANKL-induced osteoclastogenesis, as outlined in recent studies (24)(25)(26). RANKL also activates the antiapoptotic serine/ threonine kinase protein kinase B/Akt through a signaling complex involving c-Src and TRAF6, which interact with one another and with RANK after receptor engagement (27).…”

Association of polymorphisms in the Interleukin 23 receptor gene with osteonecrosis of femoral head in Korean population

“…A previous study had suggested that IL23, an IL6/IL12 cytokine member, was related to collagen-induced arthritis in mouse models and also inhibited osteoclast formation (Murphy et al, 2003;Kamiya et al, 2007). IL4 and IFN-γ, induced by IL23, have been shown to block osteoclastogenesis by means of inhibition of the transcription factors NFATc1 and c-Fos, and induction of TNF receptor-associated factor 6 (TRAF6) (Mundy, 1996;Takayanagi et al, 2002;Moreno et al, 2003;Kamel Mohamed et al, 2005;Gao et al, 2007). Therefore, these cytokines may represent a major target for the prevention of inflammation related bone diseases and promote bone metabolism.…”