Gordon J R, Galli S J
Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada.
J Exp Med. 1994 Dec 1;180(6):2027-37. doi: 10.1084/jem.180.6.2027.
Chronic allergic diseases and other disorders associated with mast cell activation can also be associated with tissue fibrosis, but a direct link between mast cell mediator release and fibroblast collagen gene expression has not been established. Using in situ hybridization, we show that the elicitation of an IgE-dependent passive cutaneous anaphylaxis (PCA) reaction in mice results in a transient, but marked augmentation of steady state levels of type alpha-1 (I) collagen mRNA in the dermis. While peak levels of collagen mRNA expression in the skin are observed 16-24 h after mast cell activation, substantial numbers of dermal cells are strongly positive for collagen mRNA at 1 and 2 h after antigen challenge, before circulating inflammatory cells are recruited into the tissues. Furthermore, experiments in mast cell-reconstituted or genetically mast cell-deficient WBB6F1-W/Wv mice demonstrate that the increased expression of collagen mRNA at sites of PCA reactions is entirely mast cell dependent. In vitro studies show that the supernatants of mouse serosal mast cells activated via the Fc epsilon RI markedly increase type alpha-1 (I) collagen mRNA levels in mouse embryonic skin fibroblasts, and also upregulate collagen secretion by these cells. The ability of mast cell supernatants to induce increased steady state levels of collagen mRNA in mouse skin fibroblasts is markedly diminished by absorption with antibodies specific for either of two mast cell-derived cytokines, transforming growth factor beta (TGF-beta 1) or tumor necrosis factor alpha (TNF-alpha), and is eliminated entirely by absorption with antibodies against both cytokines. Taken together, these findings demonstrate that IgE-dependent mouse mast cell activation can induce a transient and marked increase in steady state levels of type alpha-1 (I) collagen mRNA in dermal fibroblasts and that mast cell-derived TGF-beta 1 and TNF-alpha importantly contribute to this effect.
慢性过敏性疾病以及其他与肥大细胞活化相关的病症也可能与组织纤维化有关，但肥大细胞介质释放与成纤维细胞胶原蛋白基因表达之间的直接联系尚未确立。我们通过原位杂交表明，在小鼠中引发IgE依赖的被动皮肤过敏反应（PCA）会导致真皮中α-1（I）型胶原蛋白mRNA的稳态水平出现短暂但显著的升高。虽然在肥大细胞活化后16 - 24小时观察到皮肤中胶原蛋白mRNA表达的峰值水平，但在抗原攻击后1小时和2小时，在循环炎症细胞被募集到组织之前，大量真皮细胞的胶原蛋白mRNA呈强阳性。此外，在肥大细胞重建或基因肥大细胞缺陷的WBB6F1-W/Wv小鼠中进行的实验表明，PCA反应部位胶原蛋白mRNA表达的增加完全依赖于肥大细胞。体外研究表明，通过FcεRI活化的小鼠浆膜肥大细胞的上清液显著增加了小鼠胚胎皮肤成纤维细胞中α-1（I）型胶原蛋白mRNA的水平，并且还上调了这些细胞的胶原蛋白分泌。肥大细胞上清液诱导小鼠皮肤成纤维细胞中胶原蛋白mRNA稳态水平增加的能力，被针对两种肥大细胞衍生细胞因子之一的特异性抗体吸收后显著降低，这两种细胞因子分别是转化生长因子β（TGF-β1）或肿瘤坏死因子α（TNF-α），而被针对这两种细胞因子的抗体吸收后则完全消除。综上所述，这些发现表明IgE依赖的小鼠肥大细胞活化可诱导真皮成纤维细胞中α-1（I）型胶原蛋白mRNA的稳态水平出现短暂且显著的增加，并且肥大细胞衍生的TGF-β1和TNF-α对这一效应起着重要作用。
