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

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.

[1]  L. Leng,et al.  MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms. , 2017, American journal of physiology. Renal physiology.

[2]  H. Husi,et al.  Mitogen-Activated Protein Kinase 14 Promotes AKI. , 2017, Journal of the American Society of Nephrology : JASN.

[3]  Xiaodong Zhang,et al.  The biological function and significance of CD74 in immune diseases , 2017, Inflammation Research.

[4]  L. Leng,et al.  Plasma Levels of Macrophage Migration Inhibitory Factor and d-Dopachrome Tautomerase Show a Highly Specific Profile in Early Life , 2017, Front. Immunol..

[5]  M. Sánchez-Niño,et al.  Non-canonical NFκB activation promotes chemokine expression in podocytes , 2016, Scientific Reports.

[6]  P. Boor,et al.  Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74. , 2016, Journal of the American Society of Nephrology : JASN.

[7]  M. Sánchez-Niño,et al.  Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury. , 2016, Seminars in nephrology.

[8]  M. Sánchez-Niño,et al.  The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury. , 2015, Kidney international.

[9]  M. Sánchez-Niño,et al.  CD74 in Kidney Disease , 2015, Front. Immunol..

[10]  Weiguo Dong,et al.  AAV2/1 CD74 Gene Transfer Reduces β-amyloidosis and Improves Learning and Memory in a Mouse Model of Alzheimer's Disease , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[11]  M. Gadjeva,et al.  Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease. , 2015, The Journal of clinical investigation.

[12]  C. Putterman,et al.  Deficiency of fibroblast growth factor-inducible 14 (Fn14) preserves the filtration barrier and ameliorates lupus nephritis. , 2015, Journal of the American Society of Nephrology : JASN.

[13]  J. Leonard,et al.  Phase I study of the anti-CD74 monoclonal antibody milatuzumab (hLL1) in patients with previously treated B-cell lymphomas , 2015, Leukemia & lymphoma.

[14]  C. Trautwein,et al.  Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  M. Sánchez-Niño,et al.  TWEAK and the progression of renal disease: clinical translation. , 2014, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[16]  M. Sánchez-Niño,et al.  Fn14 in podocytes and proteinuric kidney disease. , 2013, Biochimica et biophysica acta.

[17]  G. Kéri,et al.  TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation , 2013, The Journal of pathology.

[18]  A. Chanan-Khan,et al.  Phase I, multicentre, dose‐escalation trial of monotherapy with milatuzumab (humanized anti‐CD74 monoclonal antibody) in relapsed or refractory multiple myeloma , 2013, British journal of haematology.

[19]  A. Ortiz,et al.  TNF-related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras-dependent proliferation of cultured renal fibroblast. , 2013, Biochimica et biophysica acta.

[20]  A. Sanz,et al.  MIF, CD74 and other partners in kidney disease: tales of a promiscuous couple. , 2013, Cytokine & growth factor reviews.

[21]  A. Ramos,et al.  A Polymeric Nanomedicine Diminishes Inflammatory Events in Renal Tubular Cells , 2013, PloS one.

[22]  F. Pieruzzi,et al.  Possible Pathogenetic Relationship between Fabry Disease and Renal Cell Carcinoma , 2012, American Journal of Nephrology.

[23]  R. Bucala,et al.  D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family. , 2012, Cytokine.

[24]  C. Trautwein,et al.  Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74 , 2011, Proceedings of the National Academy of Sciences.

[25]  M. Sánchez-Niño,et al.  TWEAK, a multifunctional cytokine in kidney injury. , 2011, Kidney international.

[26]  O. Lesur,et al.  The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF) , 2011, Proceedings of the National Academy of Sciences.

[27]  M. Sánchez-Niño,et al.  The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. , 2011, Journal of the American Society of Nephrology : JASN.

[28]  M. Sánchez-Niño,et al.  Globotriaosylsphingosine actions on human glomerular podocytes: implications for Fabry nephropathy. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[29]  F. Clanchy,et al.  CD74: an emerging opportunity as a therapeutic target in cancer and autoimmune disease , 2011, Expert opinion on therapeutic targets.

[30]  K. Shimada,et al.  Direct targeting of fibroblast growth factor-inducible 14 protein protects against renal ischemia reperfusion injury. , 2011, Kidney international.

[31]  Ming Zhao,et al.  The MIF Homologue D-Dopachrome Tautomerase Promotes COX-2 Expression through β-Catenin–Dependent and –Independent Mechanisms , 2010, Molecular Cancer Research.

[32]  A. Sanz,et al.  Tumor Necrosis Factor–Like Weak Inducer of Apoptosis (TWEAK) Enhances Vascular and Renal Damage Induced by Hyperlipidemic Diet in ApoE-Knockout Mice , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[33]  L. D’Adamio,et al.  CD74 interacts with APP and suppresses the production of Aβ , 2009, Molecular Neurodegeneration.

[34]  M. Sánchez-Niño,et al.  Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia , 2009, Journal of cellular and molecular medicine.

[35]  M. Sánchez-Niño,et al.  The MIF receptor CD74 in diabetic podocyte injury. , 2009, Journal of the American Society of Nephrology : JASN.

[36]  M. Sánchez-Niño,et al.  The cytokine TWEAK modulates renal tubulointerstitial inflammation. , 2008, Journal of the American Society of Nephrology : JASN.

[37]  L. Leng,et al.  Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart , 2008, Nature.

[38]  J. Bernhagen,et al.  The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity. , 2007, Molecular endocrinology.

[39]  Dannie Durand,et al.  Family , 2006, Death in the Modern World.

[40]  L. Leng,et al.  Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor , 2006, Cell Research.

[41]  D. Goldenberg,et al.  Antiproliferative activity of a humanized anti-CD74 monoclonal antibody, hLL1, on B-cell malignancies. , 2004, Blood.

[42]  Kunihiko Kobayashi,et al.  Transgene of MIF induces podocyte injury and progressive mesangial sclerosis in the mouse kidney. , 2004, Kidney international.

[43]  T. Calandra,et al.  Macrophage migration inhibitory factor: a regulator of innate immunity , 2003, Nature Reviews Immunology.

[44]  R. Atkins,et al.  Induction of MIF synthesis and secretion by tubular epithelial cells: a novel action of angiotensin II. , 2003, Kidney international.

[45]  F. Marshall,et al.  Expression profiling of renal epithelial neoplasms: a method for tumor classification and discovery of diagnostic molecular markers. , 2001, The American journal of pathology.

[46]  I. Tanaka,et al.  Crystal structure of human D-dopachrome tautomerase, a homologue of macrophage migration inhibitory factor, at 1.54 A resolution. , 1999, Biochemistry.

[47]  C. Kozak,et al.  Conserved gene structure and genomic linkage for D-dopachrome tautomerase (DDT) and MIF , 1998, Mammalian Genome.

[48]  R. Schofield,et al.  Discordant expression of major histocompatibility complex class II antigens and invariant chain in interstitial dendritic cells. Implications for self-tolerance and immunity. , 1997, Transplantation.

[49]  E. Rosengren,et al.  Isolation of a new tautomerase monitored by the conversion of D-dopachrome to 5,6-dihydroxyindole. , 1993, Biochemical and biophysical research communications.

[50]  P. Möller,et al.  Differential expression of Ia and Ia-associated invariant chain in mouse tissues after in vivo treatment with IFN-gamma. , 1986, Journal of immunology.

[51]  R. Atkins,et al.  De Novo renal expression of macrophage migration inhibitory factor during the development of rat crescentic glomerulonephritis. , 1996, The American journal of pathology.