Interleukin‐6 modulates production of T lymphocyte–derived cytokines in antigen‐induced arthritis and drives inflammation‐induced osteoclastogenesis

Wong, Peter; Quinn, J; Sims, Natalie A.; Nieuwenhuijze, Annemarie van; Campbell, Ian K.; Wicks, Ian P.

doi:10.1002/art.21537

Cited by 242 publications

(168 citation statements)

References 65 publications

(85 reference statements)

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“…Indeed, OSM participates significantly in osteoclast formation in the context of breast cancer invasion of bone, 26 and may also be involved in the increased bone destruction associated with inflammatory arthritis. 27,28 The low osteoclast numbers observed in the OSMR-null mice also suggested a role for OSM in normal physiological levels of resorption in the process of bone remodeling. 25 However, osteoclast generation from OSMRdeficient marrow cells is similar to that of wild-type bone marrow.…”

Section: Multiple Cellular Interactions Regulate Bone Structurementioning

confidence: 99%

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

Sims

Quinn

2014

BoneKEy Reports

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Bone remodeling in health and disease is carried out by osteoblasts and osteoclasts, which respectively produce bone matrix and resorb it. Endocrine and paracrine control of these cells can be direct, but they are also exerted indirectly, either by influencing progenitor cell differentiation or by stimulating paracrine signals from local accessory cells including osteocytes (which form a critical communication and regulation network within the bone matrix), macrophages and T lymphocytes. Here we review the osteotropic actions of the interleukin-6 family member cytokine oncostatin M (OSM), which is of particular interest because of its ability to stimulate bone accrual. OSM is produced within the bone microenvironment by cells of both mesenchymal and hematopoietic origin, including osteocytes, osteoblasts, macrophages and T lymphocytes, and can act via two receptor complexes: OSM receptor:gp130 and leukemia inhibitory factor receptor (LIFR):gp130. Although OSM can directly stimulate osteoblast mineralization activity and differentiation, it can also stimulate mesenchymal stem cell osteoblastic commitment at the expense of adipogenesis. In osteocytes, OSM can suppress the production of the bone formation inhibitor sclerostin, an action that is mediated by LIFR:gp130. OSM also stimulates the production of receptor activator of nuclear factor kB ligand by osteoblasts and thereby drives the formation of osteoclasts particularly in pathological conditions. Thus, cellular effects of OSM on bone metabolism include direct and indirect actions mediated by two related receptor/ligand complexes. OSM therefore provides an example of paracrine and endocrine control mechanisms that regulate bone mass by controlling both bone formation and resorption.

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Section: Multiple Cellular Interactions Regulate Bone Structurementioning

confidence: 99%

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

Sims

Quinn

2014

BoneKEy Reports

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“…Circulating t-cell numbers and function are influenced by brief periods of exercise [6,7], and a number of mechanisms have been proposed to explain these effects. First, as noted, exercise alters circulating factors and mediators (e.g., lactate, IL-6, catecholamines, growth hormone) that can affect t-cells [8][9][10]. Secondly, lymphocytes could be influenced by more direct effects such as exercise associated neurostimulation of lymph nodes and other lymph tissues [11,12].…”

Section: Introductionmentioning

confidence: 99%

Serum from exercising humans suppresses t-cell cytokine production

Radom‐Aizik¹,

Leu²,

Zaldivar³

2007

Cytokine

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Exercise affects t-cell cytokine production. Whether or not these effects are caused by circulating factors associated with physical activity (e.g., inflammatory mediators, acidosis) is unknown. To investigate this, we incubated sera (10%), obtained from 16 young-adults before (PRE) and after (END) 30-min of exercise, with commercially available Jurkat cells, a t-lymphocyte model, that, of course, had never been exposed to an exercise milieu. After 1-h and 6-h in culture, we measured in the supernatant four cytokines (each known to be altered by exercise and involved in disease pathophysiology): IL-2, TGF-β1, TNF-α, and IL-1ra. Cell proliferation was assessed with proliferating nuclear cell antigen (PNCA). Statistical analysis consisted of a linear mixed model for repeated measurement. There was no effect of exercise on t-cell production of either TGF-β1 or IL-1ra. In contrast, both IL-2 (p=0.025) and TNF-α (p=0.031) production was significantly suppressed in sera from the exercising participants. The suppression of these two cytokines occurred despite the fact that PNCA significantly increased (p<0.0001) in the END serum. In conclusion, exercise alters circulating factors that can, subsequently, influence t-cell cytokine production in vitro.

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“…Neutralising IL-17 showed the strongest ameliorating effect on disease development late in the acute phase and in the chronic arthritis phase. [37,38]. This might explain the discrepancy between IL-17 neutralisation and the lacking pro-inflammatory potential of in vitro-generated Th17 cells.…”

Section: Discussionmentioning

confidence: 99%

“…CD8 1 T cells, macrophages and neutrophils are reported to be able to express IL-17 [34][35][36]. However, CD8 1 T cells are of minor importance in AIA but macrophages and neutrophils are involved in AIA development [37,38]. This might explain the discrepancy between IL-17 neutralisation and the lacking pro-inflammatory potential of in vitro-generated Th17 cells.…”

Section: Discussionmentioning

confidence: 99%

In vitro‐induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sites

et al. 2010

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Recently, IL-17 produced by Th17 cells was described as pro-inflammatory cytokine with an eminent role in autoimmune diseases, e.g. rheumatoid arthritis. A lack of IL-17 leads to amelioration of collagen-induced arthritis. IL-17 induction in naïve CD41 T cells depends on IL-6 and TGF-b and is enhanced by IL-23. The in vivo inflammatory potential of in vitroprimed Th17 cells however, remains unclear. Here, we show that, although IL-17 neutralisation results in amelioration of murine OVA-induced arthritis, in vitro-primed Th17 cells cannot exacerbate arthritic symptoms after adoptive transfer. Furthermore, Th17 cells cannot induce an inflammatory delayed type hypersensitivity reaction because they fail to migrate into inflamed sites, possibly due to the lack of CXCR3 expression. Also, re-isolated Th17 cells acquired IFN-c expression, indicating instability of the Th17 phenotype. Taken together, the data show that IL-6, TGF-b and IL-23 might not provide sufficient signals to induce ''fully qualified'' Th17 cells.Key words: Cell migration . Inflammation . Th17 cells IntroductionIn the last years, the pro-inflammatory cytokines IL-23 and IL-17 came into focus to play a major role in inflammatory autoimmune diseases. IL-23, a heterodimeric protein consisting of p40 (shared subunit with IL-12) and p19, was identified as an important factor to induce or maintain inflammatory diseases, for p19-deficient mice are resistant to EAE and colitis [1,2]. IL-17 acts on multiple cell types to evoke the release of other pro-inflammatory cytokines like TNF-a, IL-1b or IL-6 as well as chemokines like IL-8 to attract neutrophils or macrophages to the inflamed site [3,4]. This may lead to a rising inflammatory response. In addition, IL-17 directly causes bone and cartilage destruction via upregulation of RANK-L and therefore, an eminent role of IL-17 in autoimmune diseases, like rheumatoid arthritis, was reported [5,6]. In 2006 Veldhoen et al. and others showed that the combination of IL-6 and TGF-b is sufficient to induce IL-17 expression by CD4 T cells in vitro [7]. Furthermore, by blocking Th1 and Th2 differentiation pathways, the efficiency of Th17 differentiation can be enhanced. Therefore, IL-17-producing Th cells were claimed to represent a distinct Th-cell lineage, termed Th17 cells [7][8][9]. However, IL-1b was reported to be necessary for Th17 induction in vivo and IL-6-independent pathways for IL-17 induction may exist, for IL-6-deficient mice show diminished but detectable levels of Th17 cells [10,11]. RORgT was claimed to be the Th17 lineage-specific transcription factor and sufficient to Ã These authors contributed equally to this work. To directly address the question on the role of joint-specific Th17 cells for arthritis pathogenesis we employed the OVAinduced arthritis (OIA) model. This arthritis model allows the direct analysis of OVA-specific T cells upon adoptive transfer in vivo. Using OIA and delayed type hypersensitivity (DTH) reaction, we show that in vitro-primed Th17 cells lack proinflammatory potential in vi...

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Interleukin‐6 modulates production of T lymphocyte–derived cytokines in antigen‐induced arthritis and drives inflammation‐induced osteoclastogenesis

Cited by 242 publications

References 65 publications

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

Serum from exercising humans suppresses t-cell cytokine production

In vitro‐induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sites

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