Dolgachev Vladislav, Petersen Bryan C, Budelsky Alison L, Berlin Aaron A, Lukacs Nicholas W
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Immunol. 2009 Nov 1;183(9):5705-15. doi: 10.4049/jimmunol.0901666. Epub 2009 Oct 14.
In the present studies local neutralization of allergen-induced stem cell factor (SCF) leads to decreased production of Th2 cytokines, a reduction in inflammation, allergen-specific serum IgE/IgG1, and attenuation of severe asthma-like responses. The local blockade of pulmonary SCF also resulted in a significant reduction of IL-17E (IL-25). Sorted cell populations from the lung indicated that IL-25 was produced from c-kit(+) cells, whereas Th2 cytokine production was primarily from c-kit(-) cell populations. SCF stimulated c-kit(+) eosinophils produced IL-25, whereas bone marrow-derived mast cells did not. Using 4get mice that contain a IL-4-IRES-eGFP that when transcribed coexpress GFP and IL-4, our studies identified cells that comprised a CD11b(+), GR1(+), Ly6C(+/-), c-kit(-), CD4(-), CD11c(-), MHC class II(low) cell population as a source of IL-4 in the lung after chronic allergen challenge. In the bone marrow a similar cell was identified with approximately a third of the IL-4(+) cells also expressing c-kit(+). The pulmonary and bone marrow IL-4(+) cell populations were significantly reduced upon local pulmonary anti-SCF treatment. Subsequently, when IL-25R was examined during the chronic allergen responses the expression was found on the IL-4(+) myeloid cell population that expressed CD11b(+)GR1(+). Interestingly, the IL-25R(+) cells in the bone marrow were also all CD11b(+)GR1(+), similar to the lung cells, but they were also all c-kit(+), potentially suggesting a maturation of the bone marrow cell once it enters the lung and/or is stimulated by SCF. Overall, these studies suggest a complex relationship between SCF, bone marrow-derived IL-25-responsive myeloid cells, Th2 cytokines, and chronic allergic disease.
在目前的研究中，对变应原诱导的干细胞因子（SCF）进行局部中和可导致Th2细胞因子产生减少、炎症减轻、变应原特异性血清IgE/IgG1降低以及严重哮喘样反应减弱。对肺部SCF的局部阻断还导致IL-17E（IL-25）显著减少。从肺部分选的细胞群体表明，IL-25由c-kit(+)细胞产生，而Th2细胞因子主要由c-kit(-)细胞群体产生。SCF刺激c-kit(+)嗜酸性粒细胞产生IL-25，而骨髓来源的肥大细胞则不产生。利用含有IL-4-IRES-eGFP的4get小鼠，该基因转录时可共表达GFP和IL-4，我们的研究确定了在慢性变应原攻击后，肺中构成CD11b(+)、GR1(+)、Ly6C(+/-)、c-kit(-)、CD4(-)、CD11c(-)、MHC II类（低表达）细胞群体的细胞为IL-4的来源。在骨髓中也鉴定出了类似的细胞，约三分之一的IL-4(+)细胞也表达c-kit(+)。局部肺部抗SCF治疗后，肺部和骨髓中的IL-4(+)细胞群体显著减少。随后，在慢性变应原反应期间检测IL-25R时，发现其在表达CD11b(+)GR1(+)的IL-4(+)髓样细胞群体上表达。有趣的是，骨髓中的IL-25R(+)细胞也均为CD11b(+)GR1(+)，与肺细胞相似，但它们也均为c-kit(+)，这可能表明骨髓细胞一旦进入肺部和/或受到SCF刺激就会成熟。总体而言，这些研究表明SCF、骨髓来源的IL-25反应性髓样细胞、Th2细胞因子与慢性过敏性疾病之间存在复杂的关系。
