2012年10月15日 訊 /生物谷BIOON/ --在一項(xiàng)新的研究中，來自英國(guó)鄧迪大學(xué)的研究人員發(fā)現(xiàn)控制人免疫系統(tǒng)的一個(gè)基礎(chǔ)機(jī)制可能是對(duì)抗諸如類風(fēng)濕性關(guān)節(jié)炎和銀屑病(psoriasis)之類的炎性疾病的關(guān)鍵,。
在Kris Clark博士的領(lǐng)導(dǎo)下,，這項(xiàng)研究著重研究了巨噬細(xì)胞的活性。Clark博士發(fā)現(xiàn),，一種被稱作SIK的酶在抑制抗炎性分子中發(fā)揮著重要作用,。通過關(guān)閉巨噬細(xì)胞內(nèi)的SIK功能，他能夠極大地加強(qiáng)有益的抗炎性分子的產(chǎn)生,，同時(shí)阻止導(dǎo)致炎癥的分子的產(chǎn)生,。
這項(xiàng)研究意味著關(guān)閉SIK的藥物可能能夠改善當(dāng)今用于治療包括類風(fēng)濕性關(guān)節(jié)炎和銀屑病在內(nèi)的炎性疾病的方法。
這項(xiàng)發(fā)現(xiàn)也是首次發(fā)現(xiàn)SIK和炎癥存在關(guān)聯(lián),。研究人員希望在未來更加詳細(xì)地描述SIK在免疫系統(tǒng)中發(fā)揮的作用以及關(guān)閉這種酶的化合物如何對(duì)這些作用產(chǎn)生影響,。
相關(guān)研究結(jié)果于近期刊登在PNAS期刊上。
doi: 10.1073/pnas.1215450109
PMC:
PMID:
Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages
Kristopher Clarka, Kirsty F. MacKenziea, Kasparas Petkeviciusa, Yosua Kristariyantoa, Jiazhen Zhanga, Hwan Geun Choib, Mark Peggiea, Lorna Platera, Patrick G. A. Pedriolic, Ed McIverd, Nathanael S. Grayb, J. Simon C. Arthura, and Philip Cohen
Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases.
