IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor γ1

Bendixen, Amy C.; Shevde, Nirupama K.; Dienger, Krista; Willson, Timothy M.; Funk, Colin D.; Pike, J. Wesley

doi:10.1073/pnas.041493198

Cited by 148 publications

(109 citation statements)

References 37 publications

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“…6A). The second strategy used the specific PPAR␥ inhibitor GW9662 (27). Consistent with the studies using the PPAR␥ dominant-negative mutant, pretreatment with the PPAR␥ antagonist GW9662 blocked the ability of ciglitazone, as well as cellular homogenates from UVB-irradiated cells or UVB-irradiated HAPC, to augment PMA-induced COX-2 expression in KB cells (Fig.…”

Section: Methodsmentioning

confidence: 74%

Epidermal Peroxisome Proliferator-activated Receptor γ as a Target for Ultraviolet B Radiation

Zhang¹,

Southall²,

Mezsick³

et al. 2005

Journal of Biological Chemistry

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Ultraviolet B radiation (UVB) is a pro-oxidative stressor with profound effects on skin in part through its ability to stimulate cytokine production. Peroxisome proliferator-activated receptor ␥ (PPAR␥) has been shown to regulate inflammatory processes and cytokine release in various cell types. Since the oxidized glycerophospholipid 1-hexadecyl-2-azelaoyl glycerophosphocholine (azPC) has been shown to be a potent PPAR␥ agonist, this study was designed to assess whether the PPAR␥ system is a target for UVB irradiation and involved in UVB-induced inflammation in epidermal cells. The present studies demonstrated the presence of PPAR␥ mRNA and functional protein in human keratinocytes and epithelial cell lines HaCaT, KB, and A431. The treatment of epidermal cells with the PPAR␥-specific agonist ciglitazone or azPC augmented cyclooxygenase-2 expression and enzyme activity induced by phorbol 12-myristate-13-acetate or interleukin-1␤. Lipid extracts from the cell homogenate of UVB-irradiated, but not control, cells contained a PPAR␥-agonistic activity identified by reporter assay, and this activity up-regulated cyclooxygenase-2 expression induced by phorbol 12-myristate-13-acetate. Subjecting purified 1-hexadecyl-2-arachidonoyl-glycerophosphocholine to UVB irradiation generated a PPAR␥-agonistic activity, among which the specific PPAR␥ agonist azPC was identified by mass spectrometry. These findings suggested that UVB-generated PPAR␥-agonistic activity was due to the free radical mediated nonenzymatic cleavage of endogenous glycerophosphocholines. Treatment with the specific PPAR␥ antagonist GW9662 or expression of a dominant-negative PPAR␥ mutant in KB cells inhibited UVB-induced epidermal cell prostaglandin E 2 production. These findings suggested that UVB-generated PPAR␥ activity is necessary for the optimal production of epidermal prostaglandins. These studies demonstrated that epithelial cells contain a functional PPAR␥ system, and this system is a target for UVB through the production of novel oxidatively modified endogenous phospholipids.

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Section: Methodsmentioning

confidence: 74%

Epidermal Peroxisome Proliferator-activated Receptor γ as a Target for Ultraviolet B Radiation

Zhang¹,

Southall²,

Mezsick³

et al. 2005

Journal of Biological Chemistry

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“…Several mechanisms have been proposed for these effects: antagonism of the RANKL-activated NF-B and mitogen-activate protein kinase pathways (30,31,34,43), down-regulation of NFATc1 and c-Fos expression in progenitor cells (32), regulation of Ca 2ϩ signaling (31), regulation of PPAR␥1 (33), and suppression of RANK expression (29). We previously reported that the inhibitory effects of IL-4 on the bone resorbing activity of osteoclasts are STAT6-dependent (29).…”

Section: Discussionmentioning

confidence: 99%

Complex Regulation of Tartrate-resistant Acid Phosphatase (TRAP) Expression by Interleukin 4 (IL-4)

Moreno

Stains

et al. 2009

Journal of Biological Chemistry

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“…This is interesting, as IL-4 is one of the most potent suppressors of osteoclast formation [25]. IL-4 inhibits osteoclast differentiation through directly activating PPARg [26], which is a potent transcriptional suppressor for osteoclast differentiation [27]. Moreover, IL-4 neutralizes the action of RANKL on osteoclasts by suppressing activation of NF-kB [14] and also effectively blocks TNF-a-mediated osteoclast formation [28].…”

mentioning

confidence: 99%

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

et al. 2011

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Tumour necrosis factor alpha (TNF-a) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF-a-mediated inflammation and bone resorption. Human TNF-a transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1 À/À mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-a-induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1 À/À mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-a-induced bone loss by closely interacting with IL-1 in blocking bone protective T-cell responses.Key words: Arthritis . Cytokine . IL-17 . Osteoclast . T cells IntroductionBone is continuously remodelled in life by the interaction between bone resorbing cells, termed osteoclasts, with boneforming cells, termed osteoblasts [1]. Bone resorption and bone formation are usually in physiological balance, maintaining a stable bone mass. An imbalance between bone resorption and bone formation leads to bone loss and several factors such as age, oestrogen deficiency or drug therapy alter this fine balance between osteoclasts and osteoblasts in favour of the former. Immune activation and inflammation is one the pivotal condi-Ã These authors contributed equally to this work. 413tions perturbing this fine balance of bone remodelling ultimately leading to enhanced bone loss [2]. Autoimmune inflammatory diseases, such as chronic arthritis are characterized by activation of the innate and adaptive immune system eliciting profound local and systemic bone loss. Progressive destruction of the joints is associated with pain, functional impairment and low quality of life. In addition, loss of systemic bone mass causes osteoporosis and increased fracture risk in patients with inflammatory arthritis [3]. This tight link between inflammation and bone loss is mediated by inducible expression of factors, such as M-CSF and RANKL, which are essential for osteoclast differentiation [4]. In addition, inflammatory cytokines produced by monocytes and resident mesenchymal cells are of key importance for osteoclast formation, as they regulate expression of RANKL and also sensitize monocytes for osteoclast differentiation. In this context, TNF-a, and IL-1 are of particular key importance for osteoclast formation and bone resorption in inflammatory tissue [5,6].Aside from classical pro-inflammatory mediators like ...

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IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor γ1

Cited by 148 publications

References 37 publications

Epidermal Peroxisome Proliferator-activated Receptor γ as a Target for Ultraviolet B Radiation

Epidermal Peroxisome Proliferator-activated Receptor γ as a Target for Ultraviolet B Radiation

Complex Regulation of Tartrate-resistant Acid Phosphatase (TRAP) Expression by Interleukin 4 (IL-4)

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

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