Fra-1/AP-1 Impairs Inflammatory Responses and Chondrogenesis in Fracture Healing

Yamaguchi, Toru; Takada, Yasunari; Maruyama, Kei; Shimoda, Kouji; Arai, Yoshinori; Nango, Nobuhito; Kosaki, Naoto; Takaishi, Hironari; Toyama, Yoshiaki; Matsuo, Koichi

doi:10.1359/jbmr.090603

Cited by 24 publications

(16 citation statements)

References 39 publications

(75 reference statements)

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“…Because bone formation is enhanced in Fra-1 Tg mice (9, 12, 19), we separately analyzed the healing process after tibial transverse fracture and consistently found that production of inflammatory cytokines, including TNF-a and IL-6, around the bone fracture site is impaired in these mice (20). Furthermore, using the murine macrophage cell line RAW264.7 overexpressing Fra-1 by rentivirus, Morishita et al (21) reported that Fra-1 negatively regulates LPS-induced production of TNF-a, IL-1, IL-6, and NO.…”

Section: Discussionmentioning

confidence: 97%

Fos Proteins Suppress Dextran Sulfate Sodium-Induced Colitis through Inhibition of NF-κB

Takada

Ray²,

Ikeda

et al. 2009

The Journal of Immunology

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The Fos family proteins, c-Fos and Fra-1, are components of the dimeric transcription factor AP-1, which is typically composed of Fos and Jun family proteins. We have previously shown that mice lacking c-Fos (Fos−/− mice) respond more strongly to LPS injection than do wild-type (wt) controls. We then examined the sensitivity of Fos−/− mice to acute inflammatory stress in a dextran sulfate sodium (DSS)-induced colitis model. We found that Fos−/− mice exhibited more severe weight loss, bleeding, diarrhea, and colon shortening than did wt mice, in association with higher TNF-α production and NF-κB activity in colon segments of DSS-treated Fos−/− mice. Furthermore, NF-κB inhibition suppressed severe DSS-induced colitis in Fos−/− mice. In contrast, Fra-1 transgenic (Tg) mice responded poorly to LPS injection, and Fra-1–overexpressing macrophages and fibroblasts showed reduced production of proinflammatory cytokines, NO, and NF-κB activity. Remarkably, in the DSS-induced colitis model, Fra-1 Tg mice showed less severe clinical scores of colitis than did wt mice. Consistently, proinflammatory cytokine production and NF-κB activity in colon segments of DSS-treated Fra-1 Tg mice were lower than in wt controls. These findings reveal that the absence of c-Fos and overexpression of Fra-1 respectively enhance and suppress the activation of NF-κB in DSS-induced inflammatory stress. In this paper, we propose that AP-1 transcription factors containing c-Fos or Fra-1 are negative regulators of NF-κB–mediated stress responses.

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Section: Discussionmentioning

confidence: 97%

Fos Proteins Suppress Dextran Sulfate Sodium-Induced Colitis through Inhibition of NF-κB

Takada

Ray²,

Ikeda

et al. 2009

The Journal of Immunology

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“…Fra-1 has been shown to be a negative regulator of proinflammatory cytokine production in a murine macrophage cell line and in mouse models of colitis and bone fracture, presumably through inhibiting NFkB activity (Morishita et al, 2009;Yamaguchi et al, 2009;Takada et al, 2010). Overexpression of the closely related Fos family member Fra-2 (encoded by Fosl2) induces pulmonary fibrosis .…”

Section: Discussionmentioning

confidence: 99%

“…Given the reduced production of major proinflammatory cytokines seen in Fra-1 mice (Yamaguchi et al, 2009;Takada et al, 2010), we asked whether Fra-1 mice might be resistant to inflammatory responses induced by LPS. Surprisingly, when Fra-1 mice and littermate wild-type controls were injected i.p.…”

Section: Fra-1 Enhances Lps-induced Interstitial Lung Diseasementioning

confidence: 99%

“…Similarly, loss of c-Fos in mice results in elevated nuclear factor-kB (NF-kB) activity and increased production of proinflammatory cytokines in response to lipopolysaccharide (LPS) injection (Ray et al, 2006). Furthermore, Fra-1 overexpression in mice suppresses both bone fracture-induced inflammation and dextran sulfate sodium-induced colitis (Yamaguchi et al, 2009;Takada et al, 2010). In murine macrophages, Fra-1 is a negative regulator of proinflammatory cytokine production (Morishita et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1

et al. 2011

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The role of the AP-1 transcription factor Fra-1 (encoded by Fosl1) in inflammatory responses associated with lung disease is largely unknown. Here, we show that Fra-1 overexpression in mice reduced proinflammatory cytokine production in response to injection of lipopolysaccharide (LPS), a Toll-like receptor (TLR)-ligand. Unexpectedly, Fra-1 transgenic mice died rapidly following LPS treatment, showing severe interstitial lung disease and displaying massive accumulation of macrophages and overproduction of several chemokines, including macrophage chemoattractant protein-1 (MCP-1, encoded by Ccl2). To assess the clinical relevance of Fra-1 in lung pathology, mice were treated with the anticancer drug gefitinib (Iressa), which can lead to interstitial lung disease in patients. Gefitinib-treated mice showed increased Fosl1 and Ccl2 expression and developed interstitial lung disease in response to LPS, endogenous TLR ligands and chemotherapy. Moreover, deletion of Fra-1 or blocking MCP-1 receptor signaling in mice attenuated gefitinib-enhanced lethality in response to LPS. Importantly, human alveolar macrophages showed enhanced LPS-induced FOSL1 and CCL2 expression after gefitinib treatment. These results indicate that Fra-1 is an important mediator of interstitial lung disease following gefitinib treatment.

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“…11 The observation of increased chemokine production in Fra-1 transgenic mice was not anticipated, since these mice show reduced inflammatory responses in bone and the intestinal tract. 13,14 That Fra-1 differentially modulates Tnfa and Ccl2 expression is further supported by the observation that mice lacking Fra-1 do not show skewed expression of cytokines and chemokines and are resistant to gefitinib/LPS-induced lung injury. 11 In addition, inhibition of MCP-1 by neutralizing antibody or a small-molecule inhibitor against its receptor partially prevents lung injury.…”

Section: Introductionmentioning

confidence: 90%

Gefitinib, but Not Erlotinib, is a Possible Inducer of Fra-1-mediated Interstitial Lung Disease

Takada

Matsuo

2012

Keio J. Med.

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Gefitinib is an anticancer drug developed to inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Two structurally-related EGFR tyrosine kinase inhibitors, gefitinib (Iressa) and erlotinib (Tarceva), are used as oral chemotherapy by patients with non-small-cell lung cancer. Immediately after introduction of gefitinib to clinical practice, interstitial lung disease was identified as a life-threatening adverse effect, although this condition can be well managed. It is still unclear whether gefitinib and other EGFR inhibitors induce similar adverse effects in lung. We previously established mouse models of interstitial lung disease in which gefitinib induces expression of Fosl1 (which encodes the AP-1 transcription factor Fra-1) in the presence of exogenous or endogenous Toll-like receptor ligands, leading to abnormal cytokine and chemokine expression. Here, we compared and monitored the effects of EGFR inhibitors gefitinib, erlotinib and AG1517 (PD153035) on the mRNA expression levels of Fosl1, Tnf and Ccl2. Unexpectedly, gefitinib, but not the other tyrosine kinase inhibitors, elicited the Fosl1 expression profile proposed to be predictive of interstitial lung disease, suggesting that gefitinib-induced interstitial lung disease is an off-target effect not elicited by erlotinib.

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Fra-1/AP-1 Impairs Inflammatory Responses and Chondrogenesis in Fracture Healing

Cited by 24 publications

References 39 publications

Fos Proteins Suppress Dextran Sulfate Sodium-Induced Colitis through Inhibition of NF-κB

Fos Proteins Suppress Dextran Sulfate Sodium-Induced Colitis through Inhibition of NF-κB

Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1

Gefitinib, but Not Erlotinib, is a Possible Inducer of Fra-1-mediated Interstitial Lung Disease

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