Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis
Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis
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DOI：
10.1093/jnci/dji403
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发表时间：
2005-12-07
期刊：
影响因子：
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通讯作者：
Kleeberger, SR
中科院分区：
文献类型：
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作者：
Bauer, AK;Dixon, D;Kleeberger, SR
由于慢性肺部疾病易发生肺部肿瘤，因此对相关分子机制的鉴定可以提供新的预防、诊断和治疗策略。Toll样受体（TLR）介导外源性和内源性信号进入炎症细胞因子的产生以协调适应性免疫应答。为了确定Tlr 4在慢性肺部炎症中的作用，我们比较了用功能性Tlr 4（OuJ和BALB）和突变的Tlr 4（HeJ和BALB（Lps-d））处理（每4周注射125-200 mg/kg）的近交系小鼠品系中的肺渗透性、白细胞浸润和核因子κ B（NF κ B B）和激活蛋白1（AP-1）DNA结合。我们还测量了这些小鼠在单次注射致癌物（3-甲基胆蒽; 10 μ g/kg）后的原发性肿瘤形成，随后进行BHT治疗（每周注射6次，每次125-200 mg/kg）。与具有突变的Tlr 4的小鼠相比，具有功能性Tlr 4的小鼠具有降低的肺渗透性、白细胞炎症和原发性肿瘤形成（BALB（Lps-d），平均值= 22.3个肿瘤/小鼠，相对于BALB，平均值= 13.9个肿瘤/小鼠，差异= 8.4个肿瘤/小鼠，95%置信区间= 4.6至12.1个肿瘤/小鼠; P = 0.025）。NF κ B B DNA结合活性在00中高于HeJ小鼠;然而，AP-1活性在HeJ小鼠中升高。据我们所知，这是第一个证明Tlr 4在慢性肺部炎症和肿瘤发生中的调节作用的模型。
Because chronic pulmonary diseases predispose to lung neoplasia, the identification of the molecular mechanisms involved could provide novel preventive, diagnostic, and therapeutic strategies. Toll-like receptors (TLRs) transduce exogenous and endogenous signals into the production of inflammatory cytokines to coordinate adaptive immune responses. To determine the role of Tlr4 in chronic lung inflammation, we compared lung permeability, leukocyte infiltration, and nuclear factor kappa B (NF kappa B) and activator protein 1 (AP-1) DNA binding in butylated hydroxytoluene (BHT)-treated (four weekly injections of 125-200 mg/kg each) inbred mouse strains with functional Tlr4 (OuJ and BALB) and mutated Tlr4 (HeJ and BALB(Lps-d)). We also measured primary tumor formation in these mice after single-carcinogen injection (3-methylcholanthrene; 10 mu g/kg), followed by BHT treatment (six weekly injections of 125-200 mg/kg each). Mice with functional Tlr4 had reduced lung permeability, leukocyte inflammation, and primary tumor formation (BALB(Lps-d), mean = 22.3 tumors/mouse, versus BALB, mean = 13.9 tumors/mouse, difference = 8.4 tumors/mouse, 95% confidence interval = 4.6 to 12.1 tumors/mouse; P =.025) compared with mice with mutated Tlr4. NF kappa B DNA binding activity was higher in 00 than in HeJ mice; however, AP-1 activity was elevated in HeJ mice. To our knowledge, this is the first model to demonstrate a modulatory role for Tlr4 in chronic lung inflammation and tumorigenesis.