Frontline Science: Human bone cells as a source of IL‐27 under inflammatory conditions: role of TLRs and cytokines

Osteoclasts and osteoblasts express IL‐27 under specific stimulation in vitro; IL‐27‐producing bone cells are detected in situ in human bone tissues in various inflammatory settings. IL‐27 regulates immune responses as well as hematopoiesis and bone remodeling, but its cellular sources in the bone remain unknown. In this study, we investigated whether osteoclasts and osteoblasts—the 2 cell types orchestrating bone homeostasis—could be a source of IL‐27 and identified stimuli that induce its expression in vitro. We observed that human monocyte‐derived osteoclasts expressed a broader range of TLRs than did human primary osteoblasts and that both cell types exhibited a differential induction of IL‐27 expression in response to TLR or cytokine stimulation. Whereas several TLR agonists, notably TLR4 and TLR7/8 agonists, induced substantial expression of IL‐27 by osteoclasts, stimulation of osteoblasts with agonists of TLR3 and/or TLR4—the 2 TLRs selectively expressed by these cells—resulted in no or low IL‐27 expression. In addition, IL‐27 increased TLR3 expression in osteoclasts and enhanced poly(I:C)‐mediated induction of IL‐27 in these cells. IFN‐γ, when combined with either IL‐1β plus TNF‐α, IL‐11, or CNTF, induced significant levels of IL‐27 in osteoclasts but not in osteoblasts. In the latter cells, the addition of type I IFN, together with proinflammatory cytokines, was necessary to induce substantial levels of IL‐27. Immunohistochemical studies of inflamed and remodeling bone tissue, including cases of infectious osteomyelitis and bone metastases, provided evidence that osteoclasts, osteoblasts, and occasionally osteocytes or chondrocytes, could express IL‐27 in situ. This autocrine production of IL‐27 by TLR‐ or cytokine‐activated bone cells might constitute a negative‐feedback mechanism to limit bone erosion and to dampen T cell–mediated immune pathology during bone inflammation.