2012年10月15日 讯 /生物谷BIOON/ --在一项新的研究中，来自英国邓迪大学的研究人员发现控制人免疫系统的一个基础机制可能是对抗诸如类风湿性关节炎和银屑病(psoriasis)之类的炎性疾病的关键。
在Kris Clark博士的领导下，这项研究着重研究了巨噬细胞的活性。Clark博士发现，一种被称作SIK的酶在抑制抗炎性分子中发挥着重要作用。通过关闭巨噬细胞内的SIK功能，他能够极大地加强有益的抗炎性分子的产生，同时阻止导致炎症的分子的产生。
这项研究意味着关闭SIK的药物可能能够改善当今用于治疗包括类风湿性关节炎和银屑病在内的炎性疾病的方法。
这项发现也是首次发现SIK和炎症存在关联。研究人员希望在未来更加详细地描述SIK在免疫系统中发挥的作用以及关闭这种酶的化合物如何对这些作用产生影响。
相关研究结果于近期刊登在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.
