Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Immunol. 2011 Jul 1;187(1):450-61. doi: 10.4049/jimmunol.1000964. Epub 2011 May 20.
Found in inflammatory zone (FIZZ) 2, also known as resistin-like molecule (RELM)-β, belongs to a novel cysteine-rich secreted protein family named FIZZ/RELM. Its function is unclear, but a closely related family member, FIZZ1, has profibrotic activities. The human ortholog of rodent FIZZ1 has not been identified, but human FIZZ2 has significant sequence homology to both rodent FIZZ2 (59%) and FIZZ1 (50%). Given the greater homology to rodent FIZZ2, analyzing the role of FIZZ2 in a rodent model of bleomycin-induced pulmonary fibrosis would be of greater potential relevance to human fibrotic lung disease. The results showed that FIZZ2 was highly induced in lungs of rodents with bleomycin-induced pulmonary fibrosis and of human patients with idiopathic pulmonary fibrosis. FIZZ2 expression was induced in rodent and human lung epithelial cells by Th2 cytokines, which was mediated via STAT6 signaling. The FIZZ2 induction in murine lungs was found to be essential for pulmonary fibrosis, as FIZZ2 deficiency significantly suppressed pulmonary fibrosis and associated enhanced extracellular matrix and cytokine gene expression. In vitro analysis indicated that FIZZ2 could stimulate type I collagen and α-smooth muscle actin expression in lung fibroblasts. Furthermore, FIZZ2 was shown to have chemoattractant activity for bone marrow (BM) cells, especially BM-derived CD11c(+) dendritic cells. Notably, lung recruitment of BM-derived cells was impaired in FIZZ2 knockout mice. These findings suggest that FIZZ2 is a Th2-associated multifunctional mediator with potentially important roles in the pathogenesis of fibrotic lung diseases.
在炎症区（FIZZ）2 中发现，也称为抵抗素样分子（RELM）-β，属于一种新型富含半胱氨酸的分泌蛋白家族，名为 FIZZ/RELM。其功能尚不清楚，但密切相关的家族成员 FIZZ1 具有成纤维活性。啮齿动物 FIZZ1 的人类同源物尚未被鉴定，但人类 FIZZ2 与啮齿动物 FIZZ2（59%）和 FIZZ1（50%）均具有显著的序列同源性。鉴于与啮齿动物 FIZZ2 的同源性更高，分析 FIZZ2 在博来霉素诱导的肺纤维化啮齿动物模型中的作用将更能与人类纤维性肺疾病相关。结果表明，博来霉素诱导的肺纤维化啮齿动物和特发性肺纤维化患者的肺中 FIZZ2 高度诱导。Th2 细胞因子诱导了啮齿动物和人肺上皮细胞中 FIZZ2 的表达，这是通过 STAT6 信号介导的。发现 FIZZ2 在鼠肺中的诱导对于肺纤维化是必需的，因为 FIZZ2 缺陷显著抑制了肺纤维化以及相关的细胞外基质和细胞因子基因表达的增强。体外分析表明，FIZZ2 可刺激肺成纤维细胞中 I 型胶原蛋白和α-平滑肌肌动蛋白的表达。此外，FIZZ2 对骨髓（BM）细胞具有趋化活性，特别是 BM 来源的 CD11c（+）树突状细胞。值得注意的是，FIZZ2 敲除小鼠中肺内 BM 细胞的募集受损。这些发现表明 FIZZ2 是一种与 Th2 相关的多功能介质，在纤维性肺疾病的发病机制中具有潜在的重要作用。
