A profibrotic function of IL-12p40 in experimental pulmonary fibrosis
A profibrotic function of IL-12p40 in experimental pulmonary fibrosis
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DOI：
10.4049/jimmunol.169.5.2653
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发表时间：
2002-09-01
影响因子：
4.4
通讯作者：
Lison, D
中科院分区：
文献类型：
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作者：
Huaux, F;Arras, M;Lison, D
IL-12的p40亚基（IL-12 p40），而不是异源二聚体形式IL-12 p70，在C57 BL/6小鼠二氧化硅诱导的肺纤维化的发展过程中分泌。为了描述IL-12 p40对肺部炎症和纤维化过程的贡献，我们比较了IL-12 p35缺陷小鼠（IL-12 p35（-/-），能够产生IL-12 p40）和IL-12 p40缺陷小鼠（IL-12 p40（-/-））的二氧化硅颗粒的肺反应。与野生型C57 BL/6小鼠相比，IL-12 p35-/-和IL-12 p40（-/-）动物对二氧化硅产生了明显相反的反应。尽管IL-12 p40（-/-）小鼠表现出有限的炎症和纤维化反应，但IL-12 p35-/-小鼠表现出强烈且发育良好的肺部炎症和纤维化。此外，二氧化硅诱导的肺IL-12 p40含量增加在IL-12 p35-/-小鼠中显著高于野生型对照，并且与广泛的肺纤维化和肺巨噬细胞浸润相关。通过测量肺IFN-γ/IgG 2a和IL-4/IgG 1含量估计，在这两种IL-12亚基缺陷鼠品系之间观察到的对比反应不伴有严格的1型或2型极化。在体外增殖，I型胶原蛋白的表达，以及纯化的肺成纤维细胞的肌成纤维细胞分化没有受到外源性rIL-12 p40治疗的影响。在体内，补充rIL-12 p40恢复二氧化硅处理的IL-12 p40（-/-）小鼠中受损的肺纤维化反应和巨噬细胞积聚，并且还促进野生型小鼠中的纤维化和巨噬细胞流入。总之，我们的数据表明，IL-12 p40在二氧化硅诱导的肺部炎症和纤维化中起重要作用，可能是通过加剧巨噬细胞募集。
The p40 subunit of IL-12 (IL-12p40), but not the heterodimeric form IL-12p70, is secreted during the development of silica-induced lung fibrosis in C57BL/6 mice. To delineate the contribution of IL-12p40 to the lung inflammatory and fibrotic processes, we compared the pulmonary responses with silica particles of IL-12p35-deficient mice (IL-12p35(-/-), able to produce IL-12p40) and IL-12p40-deficient mice (IL-12p40(-/-)). IL-12p35-/- and IL-12p40(-/-) animals developed strikingly contrasting responses to silica in comparison with wild-type C57BL/6 mice. Although the IL-12p40(-/-) mice exhibited limited inflammatory and fibrotic reactions, the IL-12p35-/- mice presented a robust and well-developed pulmonary inflammation and fibrosis. Furthermore, the silica-induced increase in lung IL-12p40 content was significantly higher in IL-12p35-/- mice than in wild-type controls, and was associated with extensive lung fibrosis and pulmonary macrophage infiltration. The contrasting responses observed between these two IL-12 subunit-deficient murine strains were not accompanied by a strict type 1 or type 2 polarization as estimated by the measurements of lung IFN-gamma/IgG2a and IL-4/IgG1 content. In vitro proliferation, type I collagen expression, as well as myofibroblast differentiation of purified pulmonary fibroblasts were not affected by treatment with exogenous rIL-12p40. In vivo, supplementation with rIL-12p40 restored the impaired pulmonary fibrotic response and macrophage accumulation in silica-treated IL-12p40(-/-) mice, and also promoted fibrosis and macrophage influx in wild-type mice. Together, our data suggest that IL-12p40 plays an important role in silica-induced pulmonary inflammation and fibrosis, possibly by exacerbating macrophage recruitment.