IL-27 Abrogates Receptor Activator of NF-κB Ligand-Mediated Osteoclastogenesis of Human Granulocyte-Macrophage Colony-Forming Unit Cells through STAT1-Dependent Inhibition of c-Fos

Abstract

IL-27 was first discovered as a factor supporting initial Th1 immune responses. Subsequent studies revealed that this cytokine has pleiotropic effects, including inhibition of certain immune cells, a regulatory role in hemopoietic stem cell differentiation, and antitumor activities. However, the role of human IL (hIL)-27 in human osteoclast precursors and inflammatory bone disease is unclear. Here, we examined the direct effect of hIL-27 on human osteoclastogenesis. Human bone marrow cells cultured in MethoCult medium containing human (h) GM-CSF, human stem cell factor, and hIL-3 expressed Mac-1, c-kit, and c-Fms. These cells, called hCFU-GMs, also expressed the IL-27 receptor, an IL-27Rα (WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-κB ligand induced the differentiation of tartrate-resistant acid phosphatase-positive multinucleated cells (osteoclasts) from hCFU-GMs, and hIL-27 inhibited this osteoclastogenesis in a dose-dependent manner. hIL-27 also repressed bone resorption by osteoclasts on a dentine slice. hIL-27 caused a remarkable increase in STAT1 phosphorylation and enhanced the STAT1 protein level. It also inhibited the expression of receptor activator of NF-κB ligand-induced c-Fos and cytoplasmic, calcineurin-dependent 1 NFAT (NFATc1), which are indispensable transcription factors for osteoclastogenesis. Fludarabine, a STAT1 inhibitor, and STAT1 small interfering RNA partially rescued the inhibition of osteoclastogenesis by IL-27. A WSX-1 deficiency caused severe inflammatory bone destruction primed by Escherichia coli cell wall lysate in vivo. Therefore, hIL-27 may act as an anti-inflammatory cytokine in human bone destruction, by inhibiting osteoclastogenesis from hCFU-GMs via STAT1-dependent down-regulation of the transcription factor c-Fos. Our results suggest that hIL-27 may prove useful as a therapeutic target for inflammatory bone destruction.

Interleukin-27 Acts as Multifunctional Antitumor Agent in Multiple Myeloma

“…In humans, IL-27 has been recently shown to inhibit directly in vitro osteoclast differentiation from mononuclear cells of normal individuals (42). Whether or not IL-27 can exert a similar activity in MM patients was unknown.…”

Interleukin-27 Gene Delivery for Modifying Malignant Interactions Between Prostate Tumor and Bone

“…That report was the first evidence that IL-27 could directly mediate bone cell signaling that enhanced proliferation and differentiation of mature OB and prevented OC formation in coculture with tumor cells. Other direct effects of IL-27 reported on bone cells have included blocking human bone marrow OC formation, through induction of c-Fos and NFATc1, indispensable transcription factors for osteoclastogenesis (Furukawa et al, 2009), as well as IL-27 downregulation of RANK and TREM-2 and blockage of RANKL-mediated ERK, p38, and NF-kB activation in OC precursors (Kalliolias et al, 2010). The role of IL-27 in mediating bone cell phenotypic changes also has been described as indirect, via inhibition of OC differentiation (Kamiya et al, 2007), partially through activated T cell effects on survival and OC cell fusion.…”

Interleukin‐27: A master regulator in inflammation

“…IL-27 can suppress RANKL-induced osteoclastogenesis and inhibit expression of c-Fos and calcineurindependent 1 nuclear factor of activated T cells, key transcriptional factors involved in osteoclastogenesis, implying that IL-27 may play a direct role in inhibiting bone erosion in RA (21). In addition, IL-27 has the ability to suppress the proinflammatory effects of oncostatin M (OSM)-mediated TNF␣-and inducible nitric oxide synthase-induced transcriptional pathways (22).…”