TWEAK increases CD74 expression and sensitizes to DDT proinflammatory actions in tubular cells

PLoS One. 2018 Jun 20;13(6):e0199391. doi: 10.1371/journal.pone.0199391. eCollection 2018.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Cytokine TWEAK / metabolism*
  • Female
  • Histocompatibility Antigens Class II / metabolism*
  • Inflammation / pathology*
  • Intramolecular Oxidoreductases / metabolism*
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology*
  • Macrophage Migration-Inhibitory Factors / metabolism
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Antigens, Differentiation, B-Lymphocyte
  • Cytokine TWEAK
  • Histocompatibility Antigens Class II
  • Macrophage Migration-Inhibitory Factors
  • RNA, Messenger
  • Tnfsf12 protein, mouse
  • invariant chain
  • Intramolecular Oxidoreductases
  • Mif protein, mouse
  • dopachrome isomerase

Grant support

This work was supported by FIS PI15/00298, CP14/00133, PI16/02057, PI16/01900, ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, Sociedad Española de Nefrología and Programas de actividades de I + D entre grupos de investigación de la Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. Salary support: FIS Miguel Servet MS14/00133 to MDSN and to ABS, and FIS FI14/00398 to LVR. RB and LL are supported by the US NIH.