Tournoy K G, Kips J C, Pauwels R A
Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium.
J Allergy Clin Immunol. 2001 Mar;107(3):483-91. doi: 10.1067/mai.2001.112693.
Asthma is characterized by allergen-induced airway inflammation orchestrated by TH2 cells. The TH1-promoting cytokine IL-12 is capable of inhibiting the TH2-driven allergen-induced airway changes in mice and is therefore regarded as an interesting strategy for treating asthma.
The antiallergic effects of IL-12 are only partially dependent of IFN-gamma. Because IL-12 is a potent inducer of the anti-inflammatory cytokine IL-10, the aim of the present study was to investigate in vivo whether the antiallergic effects of IL-12 are mediated through IL-10.
C57BL/6J-IL-10 knock-out (IL-10(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and subsequently exposed from day 14 to day 21 to aerosolized OVA (1%). IL-12 was administered intraperitoneally during sensitization, subsequent OVA exposure, or both.
IL-12 inhibited the OVA-induced airway eosinophilia, despite the absence of IL-10. Moreover, a shift from a TH2 inflammatory pattern toward a TH1 reaction was observed, with concomitant pronounced mononuclear peribronchial inflammation after IL-12 treatment. Allergen-specific IgE synthesis was completely suppressed only when IL-12 was administered along with the allergen sensitization. Furthermore, treating the animals with IL-12 at the time of the secondary allergen challenge resulted not only in a significant suppression of the airway responsiveness but also in an important IFN-gamma-associated toxicity.
These results indicate that IL-12 is able to inhibit allergen-induced airway changes, even in the absence of IL-10. In addition, our results raise concerns regarding the redirection of TH2 inflammation by TH1-inducing therapies because treatment with IL-12 resulted not only in a disappearance of the TH2 inflammation but also in a TH1-driven inflammatory pulmonary pathology.
哮喘的特征是由TH2细胞精心编排的变应原诱导的气道炎症。促进TH1的细胞因子白细胞介素-12（IL-12）能够抑制小鼠中由TH2驱动的变应原诱导的气道变化，因此被视为治疗哮喘的一种有前景的策略。
IL-12的抗过敏作用仅部分依赖于干扰素-γ（IFN-γ）。由于IL-12是抗炎细胞因子白细胞介素-10（IL-10）的强效诱导剂，本研究的目的是在体内研究IL-12的抗过敏作用是否通过IL-10介导。
将C57BL/6J-IL-10基因敲除（IL-10(-/-)）小鼠腹腔注射卵清蛋白（OVA）致敏，随后从第14天至第21天暴露于雾化OVA（1%）。在致敏期间、随后的OVA暴露期间或两者同时腹腔注射IL-12。
尽管缺乏IL-10，IL-12仍抑制了OVA诱导的气道嗜酸性粒细胞增多。此外，观察到从TH2炎症模式向TH1反应的转变，IL-12治疗后伴有明显的支气管周围单核细胞炎症。仅当IL-12与变应原致敏同时给药时，变应原特异性IgE合成才被完全抑制。此外，在二次变应原激发时用IL-12治疗动物不仅导致气道反应性显著抑制，还导致重要的IFN-γ相关毒性。
这些结果表明，即使在没有IL-10的情况下，IL-12也能够抑制变应原诱导 的气道变化。此外，我们的结果引发了对通过诱导TH1疗法重定向TH2炎症的担忧，因为用IL-12治疗不仅导致TH2炎症消失，还导致TH1驱动的炎症性肺部病变。
