Macrophage responses to interferon-γ are dependent on cystatin C levels

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• 作者：Katarina H. Frendé ; us ; Hanna Wallin ; Sabina Janciauskiene ; Magnus Abrahamson
• 关键词：Monocytes/macrophages ; Cytokines ; Nitric oxide ; Inflammation ; Transgenic/knockout mice
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2009
• 出版时间：November 2009
• 年：2009
• 卷：41
• 期：11
• 页码：2262-2269
• 全文大小：819 K

文摘

The aim of the present investigation was to elucidate possible effects of cystatin C on inflammatory responses mediated by macrophages. Previously it has been shown that in vitro treatment of murine peritoneal macrophages with interferon-γ (IFN-γ) causes a down-regulation of cystatin C secretion. To investigate whether such changes in cystatin C expression in turn can affect inflammatory responses mediated by macrophages, we have compared effects of IFN-γ on macrophages isolated from wild-type (cysC^+/+) and cystatin C knockout (cysC^−/−) mice. It was shown that IFN-γ-primed cysC^−/− macrophages exhibit significantly higher interleukin-10 (IL-10) but lower tumor necrosis factor-α (TNF-α) expression, and reduced nuclear factor (NF)-κB p65 activation, compared to similarly primed cysC^+/+ cells. Exogenously added cystatin C enhanced IFN-γ-induced activation of NF-κB p65 and increased mRNA levels for inducible NO synthase (iNOS) in cysC^−/− macrophages as well as levels of nitric oxide and TNF-α in the cell culture medium, in agreement with an enhanced pro-inflammatory response. Accordingly, IFN-γ-induced IL-10 mRNA expression in cysC^−/− macrophages was down-regulated by exogenously added cystatin C. Taken together, our data provide evidence that changes in cystatin C levels alter macrophage responses to IFN-γ. The latter down-regulates the production of cystatin C, which leads to a suppressed inflammatory condition with enhanced IL-10 levels and down-regulated TNF-α and NF-κB. It is concluded that cystatin C through this effect can act as an immunomodulatory molecule.