Study of a novel transcript of mouse interleukin-20 receptor, mIL-20R1a in lupus nephritis and renal crystal deposition
| Autor: | Chi-Chen Wei, 魏琪珍 |
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| Rok vydání: | 2008 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 96 We identified a novel soluble protein, mouse (m)IL-20R1a, generated by alternative splicing of the mIL-20R1 gene, which encodes one subunit of the receptor complex for mIL-19, mIL-20, and mIL-24. mIL-20R1a has 77.14% amino acid identity with the extracellular domain of mIL-20R1. However, no significant interaction between mIL-20R1a and mIL-19 or mIL-20 was detected. Therefore, we aimed to clarify whether mIL-20R1a might function as a novel effector on certain cells. Competitive binding assays demonstrated that mIL-20R1a bound to cell surfaces and resulted in AKT and JNK phosphorylation in primary mesangial cells (MCs) isolated from either the wild-type mice, DBA/W mice, or the SLE-prone mice, NZB/W mice. mIL-20R1a-treated NZB/W MCs produced higher level of chemokines and renal fibrogenic factors than mIL-20R1a-treated DBA/W MCs did. mIL-20R1a also induced generation of reactive oxygen species (ROS) in two MCs. Angiotensin II, PDGF, and LPS, all of which were involved in the pathogenesis of lupus nephritis, further enhanced mIL-20R1a expression in DBA/W MCs. Endogenous mIL-20R1a was upregulated in the bladder, colon, and spleen tissue of NZB/W mice. While the expression of mIL-20R1a in kidney, ovary, and small intestine tissue of NZB/W mice was lower than that of DBA/W mice. Elevated mIL-20R1a in the spleen tissue of NZB/W mice was expressed mainly in monocytes, B cells, and T cells. mIL-20R1a further enhanced mIL-10 production by the anti-IgM antibody-stimulated B cells in NZB/W mice. Furthermore, overexpression of mIL-20R1a in transgenic FVB/N mice resulted in the pathological change of excess calcium deposited in the kidneys. The interplay between renal epithelial cells and calcium oxalate (CaOx) was important in the crystallization involved in the formation of renal stones (nephrolithiasis). Thus, we investigated the responses of mouse renal proximal (TKPTS) and collecting (M-1) tubule cell lines to CaOx with or without mIL-20R1a. The renal epithelial cell lines exposed to CaOx in the presence of mIL-20R1a showed significantly increased LDH release; loss of cell viability through apoptosis; increased CaOx internalization; higher IL-6, TNF-alpha and MCP-1 expression; and higher ROS production. IL-6, TNF-alpha, and MCP-1 were also upregulated in the kidneys of mIL-20R1a transgenic mice. Taken together, mIL-20R1a-mediated effects on mesangial cells may involved in the disease progression of lupus nephritis. In addition, the effects of mIL-20R1a on CaOx-exposed renal epithelial cells demonstrated that mIL-20R1a functioned as an aggravating factor in promoting calcium deposition involved in the development of renal stones in mice. |
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