Banham-Hall Edward, Clatworthy Menna R, Okkenhaug Klaus
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, CB22 3AT, UK.
Open Rheumatol J. 2012;6:245-58. doi: 10.2174/1874312901206010245. Epub 2012 Sep 7.
The class 1 PI3Ks are lipid kinases with key roles in cell surface receptor-triggered signal transduction pathways. Two isoforms of the catalytic subunits, p110γ and p110δ, are enriched in leucocytes in which they promote activation, cellular growth, proliferation, differentiation and survival through the generation of the second messenger PIP3. Genetic inactivation or pharmaceutical inhibition of these PI3K isoforms in mice result in impaired immune responses and reduced susceptibility to autoimmune and inflammatory conditions. We review the PI3K signal transduction pathways and the effects of inhibition of p110γ and/or p110δ on innate and adaptive immunity. Focusing on rheumatoid arthritis and systemic lupus erythematosus we discuss the preclinical evidence and prospects for small molecule inhibitors of p110γ and/or p110δ in autoimmune disease.
1类磷脂酰肌醇-3激酶（PI3K）是脂质激酶，在细胞表面受体触发的信号转导途径中起关键作用。催化亚基的两种异构体p110γ和p110δ在白细胞中含量丰富，它们通过生成第二信使磷脂酰肌醇-3,4,5-三磷酸（PIP3）促进细胞活化、生长、增殖、分化和存活。在小鼠中对这些PI3K异构体进行基因失活或药物抑制会导致免疫反应受损，并降低对自身免疫和炎症性疾病的易感性。我们综述了PI3K信号转导途径以及抑制p110γ和/或p110δ对固有免疫和适应性免疫的影响。以类风湿性关节炎和系统性红斑狼疮为例，我们讨论了p110γ和/或p110δ小分子抑制剂在自身免疫性疾病中的临床前证据和前景。
