Waldmann Thomas A
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
J Investig Dermatol Symp Proc. 2013 Dec;16(1):S28-30. doi: 10.1038/jidsymp.2013.8.
IL-15 has a pivotal role in life and death of natural killer (NK) and CD8 memory T cells. IL-15 signals through a heterotrimeric receptor involving the common gamma chain (γc) shared with IL-2, IL-4, IL-7, IL-9, and IL-21, IL-2/IL-15 receptor β (IL-15Rβ) shared with IL-2 and a private IL-15Rα subunit. IFN- or CD40 ligand-stimulated dendritic cells coordinately express IL-15 and IL-15Rα. Cell surface IL-15Rα presents IL-15 in trans to cells that express IL-2/IL-15Rβ and γc. IL-15 is being used to treat patients with metastatic malignancy. However, IL-15 is an inflammatory cytokine involved in immunological memory including that to self, thereby playing a role in autoimmune diseases. These insights provide the scientific basis for clinical strategies directed toward diminishing IL-15 action. Dysregulated IL-15 expression was demonstrated in patients with rheumatoid arthritis, inflammatory bowel disease, psoriasis, celiac disease, and alopecia areata. The monoclonal antibody Hu-Mik-β-1 targets the cytokine receptor subunit IL-2/IL-15Rβ (CD122), blocks IL-15 transpresentation, and is being used in clinical trials in patients with autoimmune diseases. In parallel, clinical trials have been initiated involving the Jak2/3 (Janus kinase-2/3) inhibitor tofacitinib and Jak1/2 inhibitor ruxolitinib to block IL-15 signaling.
白细胞介素-15（IL-15）在自然杀伤（NK）细胞和CD8记忆T细胞的生死过程中起关键作用。IL-15通过一种异源三聚体受体发出信号，该受体涉及与IL-2、IL-4、IL-7、IL-9和IL-21共享的共同γ链（γc）、与IL-2共享的IL-2/IL-15受体β（IL-15Rβ）以及一个特定的IL-15Rα亚基。干扰素或CD40配体刺激的树突状细胞协同表达IL-15和IL-15Rα。细胞表面的IL-15Rα将IL-15反式呈递给表达IL-2/IL-15Rβ和γc的细胞。IL-15正被用于治疗转移性恶性肿瘤患者。然而，IL-15是一种参与免疫记忆（包括自身免疫记忆）的炎性细胞因子，因此在自身免疫性疾病中发挥作用。这些见解为旨在减少IL-15作用的临床策略提供了科学依据。类风湿性关节炎、炎症性肠病、银屑病、乳糜泻和斑秃患者中均显示出IL-15表达失调。单克隆抗体Hu-Mik-β-1靶向细胞因子受体亚基IL-2/IL-15Rβ（CD122），阻断IL-15反式呈递，目前正在自身免疫性疾病患者中进行临床试验。同时，已启动涉及Jak2/3（Janus激酶-2/3）抑制剂托法替布和Jak1/2抑制剂鲁索替尼以阻断IL-15信号传导的临床试验。
