Submitted on October 23, 2008
Revised on December 18, 2008
Accepted on January 5, 2009
Macrophages are not a source of injurious interleukin-18 (IL-18) in ischemic acute Kidney injury (AKI) in mice
Zhibin He, Belda Dursun, DongJin Oh, Lawrence Lu, Sarah Faubel1, and Charles L Edelstein2*
1 University of Colorado Health Sciences
2 University of Colorado Health Sciences Center
* To whom correspondence should be addressed. E-mail: charles.edelstein{at}uchsc.edu.
We previously reported in ischemic AKI in mice that caspase-1-mediated production of IL-18 is pathogenic and that macrophage depletion by liposome encapsulated clodronate (LEC) is protective. Therefore, our aim was to determine whether macrophages are a source of IL-18 in ischemic AKI in mice. On immunofluorescence staining of the outer stripe of outer medulla, the number of macrophages double stained for CD11b and IL-18 was significantly increased in AKI and significantly decreased by LEC. Adoptive transfer of RAW 264.7 cells, a mouse macrophage line that constitutively expresses IL-18 mRNA, via the tail vein, reversed the functional protection against AKI in both LEC-treated wild type and caspase-1 -/- mice. To test whether IL-18 in macrophages is necessary to cause AKI, we adoptively transferred macrophages in which IL-18 was inhibited. Peritoneal macrophages isolated from wild type mice, IL-18 binding protein transgenic (IL-18 BP Tg) mice and IL-18 -/- mice were used. IL-18 BP Tg mice overexpress human IL-18 BP and exhibit decreased biological activity of IL-18. Adoptive transfer of peritoneal macrophages from wild type as well as IL-18 BP Tg and IL-18 -/- mice reversed the functional protection against AKI in LEC treated mice. In summary, adoptive transfer of RAW cells, that constitutively express IL-18, reverses the functional protection in macrophage depleted wild type and caspase-1 -/- mice with AKI. However, adoptive transfer of peritoneal macrophages in which IL-18 function was inhibited also reverses the functional protection in macrophage depleted mice. In conclusion, IL-18 from adoptive transfer of macrophages is not sufficient to cause ischemic AKI.
