Interleukin 17 inhibits myogenic and promotes osteogenic differentiation of C2C12 myoblasts by activating ERK1,2

Abstract

The present study evaluated the role of interleukin (IL) 17 in multilineage commitment of C2C12 myoblastic cells and investigated associated signaling pathways. The results concerning the effects on cell function showed that IL-17 inhibits the migration of C2C12 cells, while not affecting their proliferation. The data regarding the influence on differentiation demonstrated that IL-17 inhibits myogenic differentiation of C2C12 cells by down-regulating the myogenin mRNA level, myosin heavy chain expression and myotube formation, but promotes their osteogenic differentiation by up-regulating the Runt-related transcription factor 2 mRNA level, cyclooxygenase-2 expression and alkaline phosphatase activity. IL-17 exerted these effects by activating ERK1,2 mitogen activated protein kinase signaling pathway, which in turn regulated the expression of relevant genes and proteins to inhibit myogenic differentiation and induce osteogenic differentiation. Additional analysis showed that the induction of osteogenic differentiation by IL-17 is independent of BMP signaling. The results obtained demonstrate the potential of IL-17 not only to inhibit the myogenic differentiation of C2C12 myoblasts but also to convert their differentiation pathway into that of osteoblast lineage providing new insight into the capacities of IL-17 to modulate the differentiation commitment.

Doxycycline Inhibits IL-17-Stimulated MMP-9 Expression by Downregulating ERK1/2 Activation: Implications in Myogenic Differentiation

“…In this line, IL-17 was shown to trigger numerous signal transduction pathways, including ERK1/2 and p38 MAPKs [4]. In accordance with our previous work [19], we confirmed here that IL-17 is able to enhance phosphorylation of ERK1/2 in C2C12 cells, and we also showed that this pathway was essential for the induction of MMP-9 expression by IL-17. Our results indicate that Doxycycline strongly inhibits IL-17-induced MMP-9 expression and ERK1/2 activation.…”

“…We have previously shown that IL-17 activates ERK1/2 in C2C12 cells [19], and, in order to clarify whether ERK1/2 pathway mediates IL-17-induced MMP-9 production and expression, C2C12 cells were treated with IL-17 in the presence of MEK1,2 inhibitor, PD98059, and the MMP-9 protein and mRNA expression were determined. As shown in Figure 5(a), cotreatment of the cells with IL-17 and MEK1,2 inhibitor significantly blocked the increment of both MMP-9 activity and mRNA expression induced by IL-17.…”

“…In addition, recent work showed that Doxy treatment can regulate both local and systemic inflammation, suggesting its importance in inflammatory myopathies [17, 18]. We have recently demonstrated the ability of IL-17 to inhibit myogenesis in vitro [19], while MMP-9 participation as well as the regulatory role of Doxy in this process has not been well defined so far.…”

The role of interleukin-17 in bone metabolism and inflammatory skeletal diseases

“…IL-17F also stimulated osteogenic differentiation of MC3T3-E1 mouse pre-osteoblast cells, as well as primary mouse mesenchymal stromal cells (29). In mouse myoblast cell line C2C12, IL-17 promoted osteogenic differentiation, while suppressing myogenic differentiation (30). Interestingly, IL-17 has been widely accepted to inhibit adipogenesis (31), suggesting that IL-17 may steer mesenchymal stem cells into an osteogenic fate (Fig.…”

The role of interleukin-17 in immune-mediated inflammatory myopathies and possible therapeutic implications

“…While IL-17 alone had no effect on CCL20 production, IL-17 amplifiedthe effects of IL-1βon IL-6 and CCL20 secretion by the muscle explants.In another study the expression of HLA class I, CFos, NF-κB and C-Jun was also found to be increased by IL-17 stimulation [106]. A recentstudy demonstrated the ability of IL-17 to inhibit myoblast migration and myogenic differentiation in an ERK1,2 dependent manner [107].In a further study IL-17 was shown to mediate this effect though the inhibition of urokinase type plasminogen inhibitor (uPA), a key molecule in skeletal myogenesis [108].…”