Adams John S, Ren Songyang, Liu Philip T, Chun Rene F, Lagishetty Venu, Gombart Adrian F, Borregaard Niels, Modlin Robert L, Hewison Martin
Orthopaedic Hospital Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, 90095, USA.
J Immunol. 2009 Apr 1;182(7):4289-95. doi: 10.4049/jimmunol.0803736.
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that induce expression of the vitamin D receptor and localized synthesis of 1,25(OH)(2)D from precursor 25-hydroxyvitamin D(3) (25OHD). To clarify the relationship between vitamin D and innate immunity, we assessed changes in hCAP expression in vivo and ex vivo in human subjects attending a bone clinic (n = 50). Of these, 38% were vitamin D-insufficient (<75 nM 25OHD) and received supplementation with vitamin D (50,000 IU vitamin D(2) twice weekly for 5 wk). Baseline 25OHD status or vitamin D supplementation had no effect on circulating levels of hCAP. Therefore, ex vivo changes in hCAP for each subject were assessed using peripheral blood monocytes cultured with 10% autologous serum (n = 28). Under these vitamin D "insufficient" conditions the TLR2/1 ligand 19 kDa lipopeptide or the TLR4 ligand LPS, monocytes showed increased expression of the vitamin D-activating enzyme CYP27b1 (5- and 5.5-fold, respectively, both p < 0.01) but decreased expression of hCAP mRNA (10-fold and 30-fold, both p < 0.001). Following treatment with 19 kDa, expression of hCAP: 1) correlated with 25OHD levels in serum culture supplements (R = 0.649, p < 0.001); 2) was significantly enhanced by exogenous 25OHD (5 nM); and 3) was significantly enhanced with serum from vivo vitamin D-supplemented patients. These data suggest that a key role of vitamin D in innate immunity is to maintain localized production of antibacterial hCAP following TLR activation of monocytes.
维生素D的活性形式，1,25 - 二羟基维生素D（1,25(OH)₂D）通过诱导抗菌肽（hCAP）增强先天免疫。在单核细胞/巨噬细胞中，这主要发生在对Toll样受体（TLR）激活的反应中，TLR激活可诱导维生素D受体的表达以及从前体25 - 羟基维生素D₃（25OHD）局部合成1,25(OH)₂D。为了阐明维生素D与先天免疫之间的关系，我们评估了在一家骨病诊所就诊的人类受试者（n = 50）体内和体外hCAP表达的变化。其中，38%的人维生素D不足（<75 nM 25OHD），并接受了维生素D补充（每周两次，每次50,000 IU维生素D₂，共5周）。基线25OHD状态或维生素D补充对hCAP的循环水平没有影响。因此，使用用10%自体血清培养的外周血单核细胞评估了每个受试者体外hCAP的变化（n = 28）。在这些维生素D“不足”的条件下，给予TLR2/1配体19 kDa脂肽或TLR4配体脂多糖（LPS），单核细胞显示维生素D激活酶CYP27b1的表达增加（分别为5倍和5.5倍，p均<0.01），但hCAP mRNA的表达降低（分别为10倍和30倍，p均<0.001）。用19 kDa处理后，hCAP的表达：1）与血清培养补充剂中的25OHD水平相关（R = 0.649，p < 0.001）；2）被外源性25OHD（5 nM）显著增强；3）被来自体内补充维生素D患者的血清显著增强。这些数据表明，维生素D在先天免疫中的关键作用是在单核细胞的TLR激活后维持抗菌hCAP的局部产生。
