Dearman R J, Basketter D A, Kimber I
Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Food Chem Toxicol. 1998 Mar;36(3):199-207. doi: 10.1016/s0278-6915(97)00143-9.
Repeated topical exposure of BALB/c strain mice to organic chemical respiratory allergens, such as trimellitic anhydride (TMA), or contact allergens such as 2,4-dinitrochlorobenzene (DNCB), provokes characteristic cytokine secretion profiles consistent with the divergent activation of discrete T cell subpopulations. Under such conditions, lymph node cells (LNC) isolated from animals exposed to TMA elaborated comparatively large amounts of the type 2 cytokines interleukin 10 (IL-10) and mitogen-inducible interleukin 4 (IL-4), but only low levels of the type 1 product interferon gamma (IFN-gamma). In contrast, DNCB-activated LNC displayed the converse (type 1) cytokine secretion profile. We have now examined cytokine production induced by topical application to mice of respiratory sensitizing platinum salts; ammonium tetrachloroplatinite II, ammonium hexachloroplatinate IV and cis-dichlorodiammine platinum II. Metal salts were dissolved in dimethyl sulfoxide (DMSO). Cytokine secretion profiles were compared with those elicited following concurrent exposure to TMA or DNCB or to the vehicle acetone:olive oil (AOO) alone. All three platinum salts and TMA stimulated vigorous IL-4 and IL-10 production compared with DNCB-activated LNC; vehicle-stimulated LNC failed to elaborate detectable levels of either cytokine. However, DNCB and the DMSO vehicle provoked substantial IFN-gamma expression, whereas exposure to AOO vehicle resulted in a considerably weaker IFN-gamma response. Levels of this cytokine induced by treatment with respiratory allergens were, in the majority of cases, substantially lower than those observed with the relevant vehicle. Indeed, an inverse dose-response relationship for IFN-gamma expression was exhibited by all three platinum salts, suggestive of the elaboration by platinum salt activated LNC of an inhibitory factor or factors for IFN-gamma. These data suggest that it may be possible to identify those metal salts with respiratory sensitizing potential as a function of induced type 2 cytokine secretion patterns.
将BALB/c品系小鼠反复局部暴露于有机化学呼吸变应原，如偏苯三酸酐（TMA），或接触变应原如2,4-二硝基氯苯（DNCB），会引发与离散T细胞亚群的不同激活相一致的特征性细胞因子分泌谱。在这种情况下，从暴露于TMA的动物中分离出的淋巴结细胞（LNC）会产生相对大量的2型细胞因子白细胞介素10（IL-10）和丝裂原诱导的白细胞介素4（IL-4），但仅产生低水平的1型产物干扰素γ（IFN-γ）。相反，DNCB激活的LNC表现出相反的（1型）细胞因子分泌谱。我们现在研究了通过局部应用呼吸致敏铂盐（四氯铂酸铵II、六氯铂酸铵IV和顺-二氯二氨铂II）诱导小鼠产生的细胞因子。金属盐溶解于二甲基亚砜（DMSO）中。将细胞因子分泌谱与同时暴露于TMA或DNCB或仅暴露于载体丙酮：橄榄油（AOO）后引发的谱进行比较。与DNCB激活的LNC相比，所有三种铂盐和TMA均刺激了强烈的IL-4和IL-10产生；载体刺激的LNC未能产生可检测水平的任何一种细胞因子。然而，DNCB和DMSO载体引发了大量的IFN-γ表达，而暴露于AOO载体导致IFN-γ反应明显较弱。在大多数情况下，呼吸变应原处理诱导的这种细胞因子水平明显低于相关载体观察到的水平。实际上，所有三种铂盐均表现出IFN-γ表达的剂量反应反比关系，提示铂盐激活的LNC产生了一种或多种IFN-γ抑制因子。这些数据表明，有可能根据诱导的2型细胞因子分泌模式来识别具有呼吸致敏潜力的金属盐。
