期刊
JOURNAL OF IMMUNOLOGY
卷 188, 期 11, 页码 5571-5584出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1102259
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资金
- Hi-Tech Research and Development Program of China (863) [2012AA092202]
- National Basic Research Program of China (973) [2012CB114404, 2012CB114402]
- National Natural Science Foundation of China [30871936, 31072234, 31172436]
- Program for Key Innovative Research Team of Zhejiang Province [2010R50026]
The roles of IL-4 and IL-4R alpha in Th2-mediated immunity have been well characterized in humans and other mammals. In contrast, few reports have been documented in ancient vertebrates. Several putative IL-4- and IL-4R alpha-like molecules were identified recently from a few fish species, providing preliminary insight into the occurrence of Th2-type immunity in teleosts. However, functional determination still is required to address this hypothesis. To this end, these two molecules were characterized functionally in zebrafish (Danio rerio). Besides the identification of a full-length IL-4R alpha molecule and an isoform lacking most of the cytoplasmic region as predicted previously, two novel alternatively spliced soluble variants with the extracellular domain only also were identified. Zebrafish IL-4R alpha (DrIL-4R alpha) shared overall conserved structural features of the IL-4R alpha family. Immunofluorescence staining showed that DrIL-4R alpha distributed on B cells. In vitro binding assays demonstrated that zebrafish IL-4 (DrIL-4) can bind specifically to DrIL-4R alpha. In vivo administration of DrIL-4 significantly upregulated B cell proliferation and Ab production. These DrIL-4-elicited immune responses were downregulated by the administration of zebrafish soluble IL-4R alpha or by DrIL-4R alpha blockade using anti-DrIL-4R alpha Abs. In addition, Th2-related cytokines or transcription factors were upregulated by DrIL-4. The DrIL-4-DrIL-4R alpha interaction promoted CD40 expression on B cells and enhanced the CD154-CD40 costimulatory response, both of which are crucial for the initiation of Th2-type immunity. To our knowledge, this is the first report showing that a possible Th2-mediated regulatory mechanism may have appeared before the divergence of teleosts and mammals. These results add greater insight into the evolutionary history of adaptive immunity. The Journal of Immunology, 2012, 188: 5571-5584.
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