Receptor Activator of NF-κB Ligand and Osteoprotegerin Regulate Proinflammatory Cytokine Production in Mice

Maruyama, Kei; Takada, Yasunari; Ray, Neelanjan; Kishimoto, Yukiko; Penninger, Josef; Yasuda, Hisataka; Matsuo, Koichi

doi:10.4049/jimmunol.177.6.3799

Cited by 99 publications

(84 citation statements)

References 39 publications

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“…In support of this concept, TRANCE-RANK signaling was previously implicated in the stimulation of IL-10 expression by PP-associated DC and the induction of oral tolerance (48). Furthermore, treatment with soluble TRANCE was recently found to dampen proinflammatory cytokine responses to LPS and other bacterial components in both in vitro and in vivo experiments (49). The elucidation of the mechanisms responsible for the specialized pattern of TRANCE expression in PP and ILF and its potential role in tolerance induction at these sites will be an important area for future studies.…”

Section: Discussionmentioning

confidence: 75%

Lymphotoxin-Independent Expression of TNF-Related Activation-Induced Cytokine by Stromal Cells in Cryptopatches, Isolated Lymphoid Follicles, and Peyer’s Patches

Taylor

Patel

Lin

et al. 2007

The Journal of Immunology

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Stromal cells play a crucial role in the organogenesis of lymphoid tissues. We previously identified VCAM-1+ stromal cells in cryptopatches (CP) and isolated lymphoid follicles (ILF) in the small intestine of C57BL/6 mice. Nonhemopoietic stromal cell networks in CP and ILF of adult mice also expressed FDC-M1, CD157 (BP-3), and TNF-related activation-induced cytokine (TRANCE). Individual stromal cells were heterogeneous in their expression of these markers, with not all stromal cells expressing the entire set of stromal cell markers. Expression of VCAM-1, FDC-M1, and CD157 on CP stromal cells was absent in alymphoplasia mice deficient in NF-κB-inducing kinase (NIK) and NIK knockout mice. Administration of lymphotoxin β receptor (LTβR)-Ig to wild-type mice on day 13 resulted in the absence of CP on day 20; delaying administration of LTβR-Ig until day 18 resulted in an 80% decrease in the number of CP on day 22 and diminished expression of VCAM-1, FDC-M1, and CD157 on the remaining CP. In sharp contrast, TRANCE expression by stromal cells was completely independent of NIK and LTβR. In addition, expression of TRANCE in ILF was concentrated just beneath the follicle-associated epithelium, a pattern of polarization that was also observed in Peyer’s patches. These findings suggest that TRANCE on stromal cells contributes to the differentiation and maintenance of organized lymphoid aggregates in the small intestine.

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Section: Discussionmentioning

confidence: 75%

Lymphotoxin-Independent Expression of TNF-Related Activation-Induced Cytokine by Stromal Cells in Cryptopatches, Isolated Lymphoid Follicles, and Peyer’s Patches

Taylor

Patel

Lin

et al. 2007

The Journal of Immunology

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“…The OPG/RANKL/RANK system in bone (6) and vasculature (7) is well known to work on bone metabolism (8) and vascular calcification (7). In addition, immune cells (6,(9)(10)(11)(12) express these molecules, and this system is believed to be associated with the regulation of inflammatory and immune responses (13,14). RANKL is expressed in CD4…”

mentioning

confidence: 99%

OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice

Shimamura

Nakagami

Osako

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

101

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Osteoprotegerin (OPG) is a soluble secreted protein and a decoy receptor, which inhibits a receptor activator of nuclear factor κB (NF-κB) ligand (RANKL)/the receptor activator of NF-κB (RANK) signaling. Recent clinical studies have shown that a high-serum-OPG level is associated with unfavorable outcome in ischemic stroke, but it is unclear whether OPG is a culprit or an innocent bystander. Here we demonstrate that enhanced RANKL/RANK signaling in OPG −/− mice or recombinant RANKL-treated mice contributed to the reduction of infarct volume and brain edema via reduced postischemic inflammation. On the contrary, infarct volume was increased by reduced RANKL/RANK signaling in OPG −/− mice and WT mice treated with anti-RANKL neutralizing antibody. OPG, RANKL, and RANK mRNA were increased in the acute stage and were expressed in activated microglia and macrophages. Although enhanced RANKL/RANK signaling had no effects in glutamate, CoCl 2 , or H 2 O 2 -stimulated neuronal culture, enhanced RANKL/RANK signaling showed neuroprotective effects with reduced expression in inflammatory cytokines in LPS-stimulated neuron-glia mixed culture, suggesting that RANKL/RANK signaling can attenuate inflammation through a Toll-like receptor signaling pathway in microglia. Our findings propose that increased OPG could be a causal factor of reducing RANKL/RANK signaling and increasing postischemic inflammation. Thus, the OPG/RANKL/RANK axis plays critical roles in controlling inflammation in ischemic brains.cerebral ischemia | neuroprotection | immune cells

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“…Osteoclast formation requires two essential factors, namely, M-CSF and receptor activator of NF-B ligand (RANKL), 3 a TNFrelated ligand (3,4). RANKL also plays important roles in cellmediated immunity and is essential for lymph node organogenesis (5)(6)(7). Hormonally regulated expression of membrane-bound RANKL by osteoblasts constitutes the major physiological control of osteoclastogenesis (8), but activated T lymphocytes also produce significant amounts of membrane-bound and soluble RANKL (9,10).…”

mentioning

confidence: 99%

IL-23 Inhibits Osteoclastogenesis Indirectly through Lymphocytes and Is Required for the Maintenance of Bone Mass in Mice

Quinn

Sims

Saleh

et al. 2008

The Journal of Immunology

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IL-23 stimulates the differentiation and function of the Th17 subset of CD4+ T cells and plays a critical role in chronic inflammation. The IL-23 receptor-encoding gene is also an inflammatory disease susceptibility gene. IL-23 shares a common subunit with IL-12, a T cell-dependent osteoclast formation inhibitor, and we found that IL-23 also dose-dependently inhibited osteoclastogenesis in a CD4+ T lymphocyte-dependent manner. When sufficiently enriched, γδ T cells also mediated IL-23 inhibition. Like IL-12, IL-23 acted synergistically with IL-18 to block osteoclastogenesis but, unlike IL-12, IL-23 action depended on T cell GM-CSF production. IL-23 did not mediate IL-12 action although IL-12 induced its expression. Male mice lacking IL-23 (IL-23p19−/−) had ∼30% lower bone mineral density and tibial trabecular bone mass (bone volume (BV)/total volume (TV)) than wild-type littermates at 12 wk and 40% lower BV/TV at 26 wk of age; male heterozygotes also had lower bone mass. Female IL-23p19−/− mice also had reduced BV/TV. IL-23p19−/− mice had no detectable osteoclast defect in trabecular bone but IL-23p19−/− had thinner growth plate hypertrophic and primary spongiosa zones (and, in females, less cartilage remnants) compared with wild type. This suggests increased osteoclast action at and below the growth plate, leading to reduced amounts of mature trabecular bone. Thus, IL-23 inhibits osteoclast formation indirectly via T cells in vitro. Under nonpathological conditions (unlike inflammatory conditions), IL-23 favors higher bone mass in long bones by limiting resorption of immature bone forming below the growth plate.

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Receptor Activator of NF-κB Ligand and Osteoprotegerin Regulate Proinflammatory Cytokine Production in Mice

Cited by 99 publications

References 39 publications

Lymphotoxin-Independent Expression of TNF-Related Activation-Induced Cytokine by Stromal Cells in Cryptopatches, Isolated Lymphoid Follicles, and Peyer’s Patches

Lymphotoxin-Independent Expression of TNF-Related Activation-Induced Cytokine by Stromal Cells in Cryptopatches, Isolated Lymphoid Follicles, and Peyer’s Patches

OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice

IL-23 Inhibits Osteoclastogenesis Indirectly through Lymphocytes and Is Required for the Maintenance of Bone Mass in Mice

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