Macrophage responses to interferon-gamma are dependent on cystatin C levels.
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-gamma (IFN-gamma) 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-gamma on macrophages isolated from wild-type (cysC(+/+)) and cystatin C knockout (cysC(-/-)) mice. It was shown that IFN-gamma-primed cysC(-/-) macrophages exhibit significantly higher interleukin-10 (IL-10) but lower tumor necrosis factor-alpha (TNF-alpha) expression, and reduced nuclear factor (NF)-kappaB p65 activation, compared to similarly primed cysC(+/+) cells. Exogenously added cystatin C enhanced IFN-gamma-induced activation of NF-kappaB p65 and increased mRNA levels for inducible NO synthase (iNOS) in cysC(-/-) macrophages as well as levels of nitric oxide and TNF-alpha in the cell culture medium, in agreement with an enhanced pro-inflammatory response. Accordingly, IFN-gamma-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-gamma. 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-alpha and NF-kappaB. It is concluded that cystatin C through this effect can act as an immunomodulatory molecule.
Frendéus
Katarina H
KH
Department of Laboratory Medicine, Division of Clinical Chemistry and Pharmacology, Lund University, University Hospital, SE-221 85 Lund, Sweden. Katarina.Hakansson@med.lu.se
Wallin
Hanna
H
Janciauskiene
Sabina
S
Abrahamson
Magnus
M
D000818:Animals; D055316:Cystatin C / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D055316:Cystatin C; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II