Tumor Suppressor CYLD Acts as a Negative Regulator for Non-Typeable Haemophilus influenza-Induced Inflammation in the Middle Ear and Lung of Mice

Non-typeable Haemophilus influenza (NTHi) is an important human pathogen causing respiratory tract infections in both adults and children. NTHi infections are characterized by inflammation, which is mainly mediated by nuclear transcription factor kappaB (NF-κB)-dependent production of inflammatory mediators. The deubiquitinating enzyme cylindromatosis (CYLD), loss of which was originally reported to cause a benign human syndrome called cylindromatosis, has been identified as a key negative regulator for NF-κB in vitro. However, little is known about the role of CYLD in bacteria-induced inflammation in vivo. Here, we provided direct evidence for the negative role of CYLD in NTHi-induced inflammation of the mice in vivo. Our data demonstrated that CYLD is induced by NTHi in the middle ear and lung of mice. NTHi-induced CYLD, in turn, negatively regulates NTHi-induced NF-κB activation through deubiquitinating TRAF6 and 7 and down-regulates inflammation. Our data thus indicate that CYLD acts as a negative regulator for NF-κB-dependent inflammation in vivo, hence protecting the host against detrimental inflammatory response to NTHi infection

マクロライドの作用機序の解明と新しい併用療法の開発

application/pdfマクロライドの少量長期投与はびまん性汎細気管支炎や慢性気管支炎、慢性副鼻腔炎に効果的であるが、その機序はまだ十分解明されていない。MKP-1は最近ステロイドなどの抗炎症薬の効果にかかわっていることが報告されているが、ムチン遺伝子発現に対しては不明である。今回我々はクラリスロマイシンにてMKP-1発現が亢進することを明らかにした。またクラリスロマイシンはp38シグナルを介してMUC5AC遺伝子発現を抑制することも示した。今回の結果はマクロライドの効果におけるMKP-1の新しい役割を明らかにムチン過分泌に対する創薬に貢献するものと考える。Low-dose, long-term macrolide therapy is effective in patients with chronic airway diseases such as diffuse panbronchitis, chronic bronchitis, and chronic sinusitis. However, the mechanism underlying this clinical efficacy remains unclear. It was recently reported that MKP-1 appears to mediate the effects of several anti-inflammatory drugs, including glucocorticoids, but the role of MKP-1 on mucin gene expression in the presence of macrolide remains unknown in human airways. Here, we show that MKP-1protein is induced by clarithromycin, and that clarithromycin suppresses TNF-α-induced MUC5AC mucin gene expression in a p38 MAPK-dependent manner in human airway epithelial cells, NCI-H292 cells. Our study thus provides new insights into the role of MKP-1 on the effect of macrolides, and may help in the development of new therapeutic strategies against mucin overproduction.2014年度～2016年度科学研究費補助金(基盤研究(C))研究成果報告書2646257

上気道慢性炎症でのリモデリングにおけるＴＧＦβ１の役割

application/pdf炎症性サイトカインのTNFalphaとTGFbeta1を加えることにより、MUC2遺伝子発現の亢進はみられた。しかしMUC5AC遺伝子発現については、TGFbeta1はTNFalpha刺激で誘導されるMUC5AC遺伝子発現を抑制していた。これは当初の予想と異なり、TGFbeta1はムチンの種類によってはリモデリングを抑制する方向に働く可能性を示唆していると思われた。また今回の結果からはMUC2とMUC5AC遺伝子発現に関しTGFbeta1は異なった細胞内シグナル伝導経路を用いていることも判明した。平成19~20年度科学研究費補助金(若手研究(Ｂ))研究成果報告書1979120

Metastasis of Thyroid Cancer to the Sternum after Total Thyroidectomy and Laryngectomy

Metastasis of thyroid cancer to the sternum is rare. Ablation is the therapy of choice for patients with metastasizing differentiated thyroid cancer, while surgical resection is an option for those with resectable bony metastasis. This report describes a case of a 65-year-old woman with a sternal tumor. The patient was treated by partial sternal resection and sternal reconstruction with new material polypropylene/expanded polytetrafluoroethylene (ePTFE) composite. The postoperative course was uneventful, and she was free of recurrence after 1 year of follow-up. We conclude that surgery should be used to manage solid bony metastasis from thyroid papillary carcinoma. Further more, a polypropylene/ePTFE composite may be useful for sternal reconstruction after thoracotomy