Regulation of Myeloid Development and Function by II-4

描述（由申请人提供）：细胞因子IL-4由TH2淋巴细胞、NKT细胞和先天免疫系统细胞（包括肥大细胞和嗜酸性粒细胞）产生。它最初被认为是B细胞增殖的刺激物，但现在很清楚，IL-4可以调节许多细胞类型的增殖、凋亡、基因表达和分化。特别是在本研究中，IL-4在调节单核-巨噬细胞谱系细胞的分化和功能活性中发挥关键作用。这些细胞来源于普通的造血祖细胞，并且可以根据细胞外环境分化成具有明显不同特征的几种细胞类型。其中一些细胞类型是单核的，如树突状细胞和巨噬细胞，而其他细胞类型则属于多核类型，包括多核巨细胞（MNG）和破骨细胞。这些细胞在肉芽肿形成和骨稳态中起关键作用。

DESCRIPTION (provided by applicant): The cytokine IL-4 is produced by TH2 lymphocytes, NKT cells, and by cells of the innate immune system including mast cells, and eosinophils. It was originally identified as a stimulator of B cell proliferation, but it is now clear that IL-4 can regulate proliferation, apoptosis, gene expression, and differentiation in many cell types. In particular for this proposal, IL-4 can play a critical role in regulating the differentiation and functional activity of cells of the monocyte-macrophage lineage. Such cells are derived from common hematopoietic progenitors and can differentiate into several cell types with markedly distinct characteristics depending on the extracellular environment. Some of these cell types are mononuclear, such as dendritic cells and macrophages, while others fall into the multinucleated category including multinucleated-giant cells (MNG), and osteoclasts. These cells can play critical roles in granuloma formation and in bone homeostasis. There have been numerous reports describing effects of IL-4 on bone biology. Previous studies, performed using co-culture systems, have demonstrated complex effects of IL-4 on both osteoblasts and myeloid-derived osteoclasts. We took advantage of a simplified system using recombinant RANKL to directly test the effect of IL-4 on osteoclasts. We have shown that IL-4 directly prevents the RANKL-induced differentiation of myeloid precursors to osteoclasts while promoting the formation of giant cells. Furthermore, we found that IL-4 inhibits bone resorption by mature osteoclasts; these responses were STAT6-dependent. We found that the inhibitory effect of IL-4 on progenitors is irreversible and is associated with changes in gene expression patterns. Based on these studies, our specific goal is to understand the molecular mechanisms by which IL-4 regulates the development of myeloid precursors away from the osteoclast fate and suppresses the functional activity of mature osteoclasts. We hypothesize that IL-4 inhibits osteoclast development and function by acting at 3 different steps in the process by (1) regulating gene expression profiles in the developing progenitors altering the differentiation fate of a multipotential precursor, (2) influencing RANK-initiated responses in committed progenitors, and (3) suppressing the bone resorbing activity of mature osteoclasts. The specific aims designed to test this hypothesis are (1) to characterize the STAT6-regulated genes responsible for the IL-4-mediated control of myeloid progenitor fate, (2) to determine the mechanism by which the IL-4-activated STAT6 pathway regulates RANK-induced responses in committed progenitors, and (3) to analyze the mechanism by which IL-4 regulates mature osteoclast function. Completion of these aims will enhance our understanding of the mechanisms by which IL-4 regulates myeloid cell development and function.