人気ブログランキング |





Compelling data from both human patients and animal model-based studies have shown that aberrant host immune response triggered by intestinal microbiota is a requisite for the onset of inflammatory diseases such as ulcerative colitis (UC) and colitis-associated colorectal cancer (15, 18, 47, 49).
ヒトの患者と動物モデルベースの研究のデータはどちらも、腸の微生物によって引き起こされる宿主の異常な免疫応答が、潰瘍性大腸炎 (UC) ならびに腸炎関連結腸直腸癌のような炎症性疾患の発症に必要であることを示していて、そのデータには説得力がある。

Although the etiology of UC is still not clear and the role of the proinflammatory cytokine IFN-γ in UC is controversial, recent Meta analysis and genome-wide association studies of large cohorts of human patients have surprisingly identified IFNG, the gene encoding for IFN-γ, as a UC susceptibility locus in humans (1, 30, 39).
UCの病因はまだ明らかではなく、炎症性サイトカインIFN-γのUCにおける役割は議論の余地があるものの、最近のメタアナリシスと大規模なコホートのゲノムワイド関連研究は、驚くべきことに、UCのヒトにおける感受性の遺伝子座としてIFNG (IFN-γをコードする遺伝子) を同定した。

IFN-γ is a proinflammatory cytokine that exerts its inflammatory function through signal transducer and activator of transcription 1 (STAT1) to regulate the expression of inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) in the colonic tissues (18).
IFN-γは炎症性サイトカインであり、シグナル伝達性転写活性化因子1 (STAT1) を通してその炎症性機能を発揮する。
STAT1は腸の組織で誘導型一酸化窒素合成酵素 (iNOS) やシクロオキシゲナーゼ2 (COX2) のような炎症性メディエーターの発現を調節する。

It has been reported that IFN-γ secretion is elevated in the peripheral blood (16) and IFN-γ expression level is increased in the inflamed colonic mucosa tissues in patients with UC (46).

The expression and activation level of STAT1 is also significantly increased in colonic tissues of patients with UC (37).

These observations thus suggest that IFN-γ might play a key role in human UC pathogenesis (16, 46) and inflammation-dependent spontaneous colorectal cancer development (2, 18).

IFN-γ is secreted by activated T cells.

Therefore, infiltration and persistence of activated T cells in the colonic tissues might be the source of IFN-γ and thereby a cause of colonic inflammation.

Indeed, whereas IL-10 knockout (Il10−/−) mouse exhibits intolerance to intestinal microbiota and goes on to develop spontaneous colitis, Il10−/−Rag2−/− mouse fails to develop colitis, suggesting that UC is a T cell-mediated inflammatory disorder (27, 47).
実際、IL-10ノックアウト (Il10−/−) マウスは腸の微生物に対して過敏性を示し、腸炎を自然発症するが、Il10−/−とRag2−/−のダブルノックアウトマウスは腸炎を発症しない。

A promising class of agents with both preventive and therapeutic potential to counteract inflammation-mediated UC and colorectal cancer is short-chain fatty acids, most notably butyrate (10, 22, 43).

Butyrate is a major metabolite in colonic lumen arising from bacterial fermentation of dietary fiber and has been shown to be a critical mediator of the colonic inflammatory response (10, 21–22, 24, 40).

One mechanism underlying butyrate function in suppression of colonic inflammation is inhibition of the IFN-γ/STAT1 signaling pathways (23, 40).

Butyrate may exert its anti-inflammatory function through acting as a histone deacetylase (HDAC) inhibitor (10–11, 48); however, the specific molecular targets of butyrate as a HDAC inhibitor and molecular mechanisms of inhibition are not well-defined.
酪酸はヒストン脱アセチル化酵素 (HDAC) の阻害剤として作用することでその抗炎症機能を発揮する可能性がある。

We conducted an in-depth analysis of butyrate function in both T cells and colonic epithelial cells and determined that butyrate delivers a double-hit to inhibit inflammation:

first, butyrate inhibits IFN-γ-induced STAT1 activation and iNOS upregulation to suppress inflammation in colonic epithelial and carcinoma cells;

second and more importantly, butyrate inhibits Fas promoter-bound HDAC1 activity to induce Fas promoter hyperacetylation and Fas upregulation to enhance Fas-mediated apoptosis of T cells, resulting in termination of the uncontrolled T cell activation, thereby, eliminating the source of inflammation in the colonic tissue.



by travelair4000ext | 2014-04-09 17:57 | 翻訳  

<< GPR109Aと炎症 酪酸と炎症01 >>