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

Takada, Yasunari; Ray, Neelanjan; Ikeda, Eiji; Kawaguchi, Tomohiro; Kuwahara, Masayoshi; Wagner, Erwin F.; Matsuo, Koichi

doi:10.4049/jimmunol.0901196

Cited by 30 publications

(25 citation statements)

References 47 publications

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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: 55%

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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Section: Introductionmentioning

confidence: 55%

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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“…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%

“…As Fra-1 and other Fos proteins negatively regulate NF-kB (Takada et al, 2010), an important regulator of cell survival and inflammation (Aggarwal, 2003), we analyzed nuclear localization of NF-kB and apoptosis of lung cells. As expected, Fra-1 expression suppressed nuclear localization of the NF-kB subunit p65 (Supplementary Figure S1c) and enhanced apoptosis in the lung as demonstrated by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) analysis (Supplementary Figure S1d).…”

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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Chlorogenic Acid Suppresses miR‐155 and Ameliorates Ulcerative Colitis through the NF‐κB/NLRP3 Inflammasome Pathway

Zeng

Zhang

Wang

et al. 2020

Molecular Nutrition Food Res

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Scope: The over-activation of the nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome plays an important role in the pathogenesis of ulcerative colitis (UC). Chlorogenic acid (CGA) exposure is identified as an effective strategy for repressing inflammatory responses. Methods and results: In this study, the NLRP3 inflammasome model with LPS/ATP-induced RAW264.7 cells in vitro and dextran-sulfate-sodium (DSS)-induced colitis in mice are used to evaluate the effect of CGA on NLRP3 inflammasome-related signaling. The results suggest that CGA suppressed the expression of NLRP3 inflammasome-related genes (apoptosis-associated speck-like protein containing CARD (ASC), cysteine-requiring aspartate protease (Caspase)-1 p45, Caspase-1 p20, pro-/cleaved-interleukin (IL)-1 , pro-/cleaved-IL-18), p-nuclear factor kappa B (NF-B) protein, and miR-155 in mice with colitis. Gain-and loss-of-function studies of miR-155 are performed to elucidate its role in inflammation. Moreover, activation of the NF-B/NLRP3 inflammasome pathway and miR-155 expression is investigated. CGA exposure in lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-stimulated RAW264.7 cells leads to a decrease in p-NK-B and NLRP3 inflammasome-related proteins, which is dependent on the downregulation of miR-155 expression. Conclusions: These findings indicate that CGA prevented colitis by downregulating miR-155 expression and inactivating the NF-B/NLRP3 inflammasome pathway in macrophages. The current study has promising therapeutic implications in the treatment of UC.

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

Cited by 30 publications

References 47 publications

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

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

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

Chlorogenic Acid Suppresses miR‐155 and Ameliorates Ulcerative Colitis through the NF‐κB/NLRP3 Inflammasome Pathway

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