CD74 is a multifunctional
protein and a receptor for
Macrophage Migration Inhibitory Factor (MIF) and MIF-2 / D-
dopachrome tautomerase (
DDT)
cytokines, upregulated in
diabetic kidney disease. However, the drivers of CD74 expression and
DDT function in kidney cells are poorly characterized. TWEAK is a proinflammatory
cytokine that promotes kidney injury. We have now identified CD74 gene expression as upregulated in the kidneys in response to systemic TWEAK administration in mice, and have characterized the in vivo CD74 expression and the functional consequences in cultured cells. TWEAK administration to mice resulted in a progressive time-dependent (up to 24h) upregulation of kidney CD74
mRNA (RT-PCR) and
protein (Western blot). Furthermore, the CD74
ligands MIF and
DDT were also upregulated at the
protein level 24h after TWEAK administration. Immunohistochemistry localized the increased CD74, MIF and
DDT expression to tubular cells. In cultured tubular cells, TWEAK increased CD74
mRNA and
protein expression dose-dependently, with a temporal pattern similar to in vivo. TWEAK-induced CD74 localized to the cell membrane, where it can function as a
cytokine receptor. For the first time, we explored the actions of
DDT in tubular cells and found that
DDT amplified the increase in MCP-1 and
RANTES expression in response to TWEAK. By contrast,
DDT did not significantly modify TWEAK-induced Klotho downregulation. In conclusion, TWEAK upregulates CD74 and its
ligands MIF and
DDT in renal tubular cells. This may have functional consequences for kidney injury since
DDT amplified the inflammatory response to TWEAK.