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

Abstract

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.

IL-27: a double agent in the IL-6 family

“…While these activities pertain primarily to the control of adaptive immunity, both cytokines have influences on stromal tissue responses to inflammation. For example, IL-6 and IL-27 play important roles in bone remodelling, where an imbalance between bone resorption and formation contributes to bone destruction in inflammatory arthritis [74][75][76][77]. Here, Il27ra-deficient mice with experimental arthritis displayed severe synovitis and synovial hyperplasia, and an increased incidence of focal bone erosions [59].…”

Glycosaminoglycans bind human IL‐27 and regulate its activity

“…Whereas heparin is mostly produced by mast cells and basophils and may regulate cytokine activity during allergy, HS is produced by many cell types and may regulate cytokine activity in various immunological conditions, including pregnancy, tissue injury, inflammation, sepsis, or cancer, where increased soluble GAG levels are observed [18,36]. Because IL-27 levels are also increased in these conditions [3][4][5][37][38][39], negative regulation by soluble GAGs may constitute a feed-back mechanism to dampen its activity. IL-27 is a multi-faceted cytokine, and the functional consequences of inhibition of IL-27 activity by soluble GAGs may be either pro-or anti-inflammatory depending on the context.…”

“…IL-27 is a heterodimeric cytokine of the IL-12 family composed of two subunits, EBV induced gene 3 (EBI3) and p28 [1,2]. It is expressed by activated APCs such as macrophages and dendritic cells, as well as non-immune cells including placental cells and bone cells [2][3][4][5]. Its receptor is a heterodimeric complex that comprises IL-27Rα (formerly called TCCR or WSX-1) and gp130, and activates the STAT pathway, predominantly STAT1 and STAT3 [6].…”

IL-27/IL-27RA signaling may modulate inflammation and progression of benign prostatic hyperplasia via suppressing the LPS/TLR4 pathway

“…Studies have shown that IL-27 is induced by stimulation of TLR ligands or infectious agents (44)(45)(46). Although IL-27 is primarily produced by activated antigen presenting cells including dendritic cells and macrophages, several studies have revealed the capability of non-immune cells to express IL-27 (47,48). Additionally, the IL-27 receptor is found not only on innate or adaptive immune cells, but also on non-hematopoietic cells such as epithelial cells, fibroblasts, and keratinocytes (48).…”